WO2021211959A2

WO2021211959A2 - Methods and compositions for treating drug induced steatohepatitis

Info

Publication number: WO2021211959A2
Application number: PCT/US2021/027670
Authority: WO
Inventors: Heather Kay Webb HSU; Kris KOWDLEY; Michael Carleton; William Michael Gallatin
Original assignee: Inipharm, Inc.
Priority date: 2020-04-18
Filing date: 2021-04-16
Publication date: 2021-10-21
Also published as: WO2021211959A3

Abstract

Disclosed herein are methods related to the treatment drug induced liver injury (DILI) and more specifically drug induce steatohepatitis (DISH); the method comprising administration of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor.

Description

METHODS AND COMPOSITIONS FOR TREATING DRUG INDUCED

STEATOHEPATITIS

CROSS-REFERENCE

[0001]This application claims the benefit of U. S. Provisional Application Serial No. 63/012,091 filed April 18, 2020 which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] Drug induced liver injury (DILI) is a leading cause of acute liver failure and transplantation in western countries; and although rare, represents a serious clinical problem due to its unpredictable nature and possibly fatal course. The liver plays a central role in drug metabolism and clearance and is therefore susceptible to DILI. Liver injury remains the most common cause of clinical trial termination and a main cause of post-marketing drug withdrawals. DILI may occur in a dose-dependent way, yet the majority of cases are idiosyncratic and dose independent.

[0003] Non-alcoholic fatty liver disease (NAFLD) is recognized as a leading cause of liver disease in the western world and has increased in frequency over recent decades. The prevalence of NAFLD ranges from 20 to 30% in the general population, depending on diagnostic criteria and the specific definition applied, with rates exceeding 50% in diabetic and obese patients. NAFLD includes a spectrum of liver diseases ranging from simple hepatic steatosis to non alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). Drug induced steatosis (DIS) or steatohepatitis (DISH) is a rare form of DILI with fewer than 2% of all cases of NASH attributed to drugs. Drugs capable of inducing steatosis and steatohepatitis can be divided into three groups: drugs that induce metabolic changes and can precipitate latent NASH (e.g., tamoxifen), drugs that cause steatosis and steatohepatitis independently (e.g., amiodarone, perhexiline maleate), and drugs that induce sporadic events of steatosis/steatohepatitis (e.g., carbamazepine).

[0004] The potential reversibility of the initial liver injury, preventing the development of severe liver injury and ultimately liver fibrosis, underlines the importance of early recognition of this unique hepatotoxic effect and early administration of an effective therapy. Better understanding of the molecular mechanisms involved and potential risk factors, as well as the intricate relationship with metabolic NAFLD, may offer potential clues in identifying patients more susceptible to this type of drug injury and better understanding of the mechanisms leading to metabolic steatohepatitis. SUMMARY OF THE INVENTION

[0005] Provided herein are methods for treating drug induced liver injury (DILI), the method comprising administering to a subject in need thereof a HSD17B13 inhibitor. The subject in need thereof is undergoing or has undergone treatment with a therapy that cause liver injuries such as steatohepatitis.

[0006] Provided herein is a method of treating, preventing, or delaying drug induced liver injury (DILI) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the drug induced liver injury is caused by a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the drug induced liver injury is caused by a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the drug induced liver injury is caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the drug induced liver injury is caused by a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, the NSAID is pirprofen. In some embodiments, the drug induced liver injury is drug induced steatosis (DIS). In some embodiments, the drug induced liver injury is drug induced steatohepatitis (DISH). In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the drug has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0007] A method of treating drug induced steatohepatitis (DISH) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17- beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the drug induced steatohepatitis is caused by a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the drug induced steatohepatitis is caused by a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the drug induced steatohepatitis is caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the drug induced steatohepatitis is caused by a nonsteroidal anti inflammatory drugs (NSAID). In some embodiments, theNSAID is pirprofen. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the drug has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. [0008] A method of treating drug induced steatohepatitis (DISH) caused by a cancer drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the cancer drug are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the cancer drug are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the cancer drug has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransf erase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0009] A method of treating drug induced steatohepatitis (DISH) caused by a cardiovascular drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the cardiovascular drug is amiodarone. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the drug are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the drug has been discontinued. A method of treating drug induced steatohepatitis (DISH) caused by a tamoxifen in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, tamoxifen is administered to treat breast cancer. In some embodiments, tamoxifen is administered to prevent contralateral breast cancer. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and tamoxifen are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and tamoxifen are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once tamoxifen has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.

In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0010] A method of treating drug induced steatohepatitis (DISH) in a subject that has undergone treatment for a cancer comprising breast cancer, ovarian cancer, non-small cell lung cancer, lung cancer, head cancer, neck cancer, and colon cancer, the method comprising administering a therapeutically effective amount of a HSD17B 13 inhibitor to the subject. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer has been treated with tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer has been treated with tamoxifen. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the cancer treatment are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the cancer treatment are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the cancer treatment has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol - 3-phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPARa), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory - Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0011] A method of treating drug induced steatohepatitis (DISH) caused by a selective estrogen receptor modulator (SERM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the SERM is tamoxifen or toremifene. In some embodiments, the SERM is tamoxifen. In some embodiments, the SERM is administered to treat breast cancer. In some embodiments, the SERM is administered to prevent contralateral breast cancer. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the SERM are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the SERM has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol - 3-phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory - Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0012] A method of treating drug induced steatohepatitis (DISH) caused by an antifolate in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the antifolate is methotrexate. In some embodiments, the antifolate is administered to treat cancer. In some embodiments, the antifolate is administered to treat rheumatoid arthritis. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the SERM are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the SERM has been discontinued. In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.

[0013] A method of preventing a decrease in hepatocyte triglyceride secretion in a subject that has been administered or is being administered an additional therapeutic agent, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the additional therapeutic agent is a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the additional therapeutic agent is a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the additional therapeutic agent is a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, the NSAID is pirprofen. In some embodiments, the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments, the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some

-li embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject simultaneously. In some embodiments, the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject sequentially. In some embodiments, the HSD17B13 inhibitor is administered once the additional therapeutic agent has been discontinued.

[0014] In some embodiments, the method further comprises reducing liver triglyceride content (TG) in the subject. In some embodiments, the method further comprises reducing plasma alanine aminotransferase (ATL) levels in the subject. In some embodiments, the method further comprises reducing plasma aspartate aminotransferase (AST) levels in the subject. In some embodiments, the method further comprises reducing plasma adipose differentiation-related protein (Adrp) levels in the subject. In some embodiments, the method further comprises reversing insulin resistance in the subject. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipogenic genes in the subject. In some embodiments, the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3. In some embodiments, the method further comprises reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject. In some embodiments, the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl-CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase-2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject. In some embodiments, the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl- CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short- chain acyl-CoA dehydrogenase (Scad). In some embodiments, the method further comprises increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject. In some embodiments, the method further comprises reducing hepatic inflammation, apoptosis, or fibrosis in the subject. In some embodiments, the method further comprises reducing hepatocellular ballooning or Mallory-Denk Bodies (MDBs) in the subject. In some embodiments, the method further comprises reducing oxidative stress in the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

PET ATT, ED DESCRIPTION OF THE INVENTION [0016] Methods and compositions disclosed herein are used for modulating HSD17B13 activities to protect patients receiving targeted therapies that are known to cause steatohepatitis, a precursor of severe or chronic liver injury. HSD17B13 inhibitors can be used to expand the usefulness of drugs by protecting patients from liver damage resulting from targeted therapy, such as chemotherapy induced hepatic steatosis and progression to steatohepatitis.

Definitions

[0017] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0018] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

[0019] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0020] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0021] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0022] As used herein, the term ‘about’ a number refers to that number plus or minus 10% of that number. The term ‘about’ a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0023] “HSD17B13” means hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13. For example, in some embodiments, HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13 (including genomic DNA comprising introns and exons). HSD17B13 can also refer to any amino acid sequence of HSD17B13 (may include secondary or tertiary structures of the protein molecule), encoded by a DNA sequence and/or RNA sequence. The target may be referred to in either upper or lower case.

[0024]The term “fragment” or “derivative” when referring to a protein (e.g., HSD17B13) generally means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s). For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins.

[0025] The term “modulate,” or “modify” as used interchangeably herein, generally means to interact with a target protein (e.g., HSD17B13) either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.

[0026] As used herein, the term “modulator” generally refers to a compound that alters an activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor (e.g., HSD17B13 inhibitor), which decreases the magnitude of one or more activities of a target (e.g., a HSD17B13 protein). In certain embodiments, an inhibitor completely prevents one or more activities of a target. In certain embodiments, a modulator changes the cellular distribution of the target (e.g., a HSD17B13 protein).

[0027] As used herein, the term “target activity” generally refers to a biological activity capable of being modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, and amelioration of one or more symptoms associated with a liver disease or condition.

[0028] The terms “kit” and “article of manufacture” are used as synonyms.

[0029] The term “subject,” “patient,” or “individual” generally encompasses mammals, non mammals, and a biological entity containing expressed genetic materials. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The subject may be diagnosed or suspected of being at high risk for a liver condition or disease. In some cases, the subject may be diagnosed or suspected of being at risk for a condition or disease that needs to receive a particular therapy, which could cause or exacerbate a liver condition or disease. In some cases, the subject is not necessarily diagnosed or suspected of being at risk for the liver disease or condition.

[0030] The terms “treat,” “treating” or “treatment,” as used herein in reference to a pharmaceutical or other intervention regimen, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0031] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, prevention of sequelae, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0032] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0033] The term “pharmaceutically acceptable,” as used herein, generally refers a material, such as a carrier, diluent, or formulation, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0034] The term “pharmaceutical composition” generally refers to a mixture of a compound (e.g., a HSD17B13 inhibitor), described herein with other chemical components, such as carriers, stabilizers, diluents, surfactants, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, subcutaneous, intramuscular, pulmonary and topical administration.

[0035] The terms “effective amount” or “therapeutically effective amount,” as used herein, generally refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition, required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0036] In prophylactic applications, compositions described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, disorder or condition, such as a liver disease or condition to prevent the subject from developing the liver disease or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the subject's state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0037] The term “carrier,” as used herein, generally refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues. [0038] The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.

Drug Induced Liver Injury

[0039] Disclosed herein are methods for treating drug induced liver injury (DILI). In some embodiments, the drug induced liver injury is drug induced steatosis (DIS). In some embodiments, the drug induced liver injury is drug induced steatohepatitis (DISH). In some embodiments, the drug induced liver injury is hepatic sinusoidal Injury. In some embodiments, the drug induced liver injury is liver carcinoma.

[0040] Many pharmacological compounds designed to target and treat certain diseases or conditions, such as cytotoxic chemotherapies targeting various forms of cancer ameliorate symptoms and prolong survival of patients suffering from cancer or other diseases. However, those pharmacological compounds come with a price because they exhibit many adverse side effects. For example, since a patient’s liver has a rich blood supply and plays an active role in the metabolism of those pharmacological compounds, the adverse side effects generally may include hepatic injuries. Clinically, many patients receiving chemotherapy develop lipid metabolism disorders. In addition, the administration of chemotherapy to patients with lipid metabolism disorders may increase the risk of liver damage. Chemotherapy induces various histological changes of the liver parenchyma including steatosis, chemotherapy-associated steatohepatitis (CASH), or sinusoidal injury sinusoidal obstruction syndrome (SOS).

[0041] The mechanism of chemotherapy -induced hepatic injury may be secondary to production of reactive oxygen species (ROS), intended to induce tumor cell apoptosis. Previously steatotic livers were thought to be most susceptible to chemotherapy-induced injury due to impaired regenerative capability and abnormal innate immunity. Chemotherapies and other pharmacological compounds which induce hepatic steatosis and can cause more severe liver injury are often not discontinued to address increased risk of liver injury since the disease being treated, such as breast or lung cancer, can be lethal. Additionally, based on current prevalence in the US general population approximately 20-30% of patients being treated with hepatic steatosis-inducing drugs are likely to have non-alcoholic fatty liver disease (NAFLD) putting them at even greater risk of liver injury. Please see Table 1 below for examples of drugs that cause steatohepatitis. The examples listed in Table 1 are meant to be non-exhaustive and non limiting. There are other pharmacological compounds that may cause liver injuries. Table 1. Examples of drugs that cause steatohepatitis

[0042] In some embodiments, the drug induced liver injury is caused by a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen.

[0043] In some embodiments, the drug induced liver injury is caused by a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.

[0044] In some embodiments, the drug induced liver injury is caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the drug induced liver injury is caused by a nonsteroidal anti inflammatory drugs (NSAID). In some embodiments, theNSAID is pirprofen.

[0045] Disclosed herein are methods of treating, preventing, or delaying drug induced liver injury (DILI) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the drug induced liver injury is caused by a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the drug induced liver injury is caused by a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the drug induced liver injury is caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the drug induced liver injury is caused by a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, theNSAID is pirprofen. In some embodiments, the drug induced liver injury is drug induced steatosis (DIS). In some embodiments, the drug induced liver injury is drug induced steatohepatitis (DISH).

[0046] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the drug induced steatohepatitis is caused by a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the drug induced steatohepatitis is caused by a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the drug induced steatohepatitis is caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the drug induced steatohepatitis is caused by a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, the NSAID is pirprofen. [0047] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a cancer drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen.

[0048] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a cardiovascular drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the cardiovascular drug is amiodarone.

[0049] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. [0050] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, the NSAID is pirprofen or ibuprofen. In some embodiments, the NSAID is pirprofen.

[0051] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a tamoxifen in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, tamoxifen is administered to treat breast cancer. In some embodiments, tamoxifen is administered to prevent contralateral breast cancer.

[0052] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) in a subject that has undergone treatment for a cancer comprising breast cancer, ovarian cancer, non small cell lung cancer, lung cancer, head cancer, neck cancer, and colon cancer, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the cancer is breast cancer.

[0053] In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer has been treated with tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer has been treated with tamoxifen.

[0054] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by a selective estrogen receptor modulator (SERM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the SERM is tamoxifen or toremifene. In some embodiments, the SERM is tamoxifen. In some embodiments, the SERM is administered to treat breast cancer. In some embodiments, the SERM is administered to prevent contralateral breast cancer.

[0055] Also disclosed herein is a method of treating drug induced steatohepatitis (DISH) caused by an antifolate in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the antifolate is methotrexate. In some embodiments, the antifolate is administered to treat cancer. In some embodiments, the antifolate is administered to treat rheumatoid arthritis.

[0056] A method of preventing a decrease in hepatocyte triglyceride secretion in a subject that has been administered or is being administered an additional therapeutic agent, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject. In some embodiments, the additional therapeutic agent is a cancer drug. In some embodiments, the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof. In some embodiments, the cancer drug is tamoxifen. In some embodiments, the additional therapeutic agent is a cardiovascular drug. In some embodiments, the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof. In some embodiments, the additional therapeutic agent is a psychiatric drug. In some embodiments, the psychiatric drug is amitriptyline, clozapine, or any combination thereof. In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drugs (NSAID). In some embodiments, the NSAID is pirprofen.

Steatosis

[0057] Steatosis is a type of fatty liver disease characterized by fat accumulation in liver without inflammation . The effect of mild to moderate steatosis without associated inflammation on postoperative outcome is likely to be small. In patients with steatosis who underwent major liver resection, steatosis is associated with infection-related complications but not with major complications or postoperative mortality. In a study of patients who had major hepatectomy, patients with steatosis had increased blood loss, more postoperative complications, and a longer mean intensive-care-unit stay per patient as compared with matched control patients with healthy livers. Fluorouracil (5-FU), which remains the backbone of modern chemotherapy, has been linked to the development of steatosis. Reports indicate the development of steatosis in 30 to 47% of patients after 5-FU therapy, although some changes may be reversible.

Steatohepatitis

[0058] Steatohepatitis is a type of fatty liver disease characterized by inflammation of the liver with concurrent fat accumulation in liver. Irinotecan is clearly associated with steatohepatitis, with a rate of 20.2% seen in patients administered this drug, compared with 4.4% in those not having chemotherapy. This effect is exacerbated by baseline obesity. One study shows that steatohepatitis is found in 24.6% in those with a BMI of 25 kg/m² or more who were administered irinotecan, but only 12.1% in irinotecan treated patients with a BMI less than 25 kg/m². Steatohepatitis increases the risk of liver failure and postoperative complications following major hepatectomy.

Hepatic Sinusoidal Injury

[0059] Sinusoidal injury ranges from sinusoidal dilation to hepatic sinusoidal obstruction syndrome, also termed venoocclusive disease, which can progress to regenerative nodular hyperplasia. Injury to the sinusoidal endothelial cells lining the sinusoids, the initial event, leads to subintimal thickening and extravasation of erythrocytes into the subendothelial space of Disse (perisinusoidal space). Sinusoidal endothelial cells and erythrocytes embolize in sinusoids and block venous outflow, resulting in hepatic congestion and sinusoidal dilatation. At later stages, a fibrotic reaction in the sinusoids can lead to obliteration of central venules, leading to hepatic sinusoidal obstruction syndrome. Rates of injury are universally higher in patients receiving oxaliplatin-based chemotherapy. Studies show that oxaliplatin is associated with a 10-fold increase in sinusoidal dilation compared with no chemotherapy (18.9% versus 1.9%). In one study involving administration of chemotherapy, high-grade injuries were much more prominent in the group administered chemotherapy (41%) compared to the control group (0%). Oxaliplatin and other platinum compounds lead to the generation of ROS and could result in depletion of glutathione from sinusoidal endothelial cells (SECs). Cisplatin has been shown to cause actin dissociation, which can upregulate matrix-metalloproteinases-9 (MMP-9) activity. Morbidity following hepatectomy is significantly higher in patients with evidence of sinusoidal obstruction syndrome, although there is no increase in mortality. Sinusoidal injury also significantly increases hospital stay. Oxaliplatin is associated with an increased transfusion requirement compared to patients receiving 5 FU/leucovorin or no chemotherapy. It has been suggested that increased blood loss is directly attributable to these vascular lesions.

Additional Pathologies

[0060] In some embodiments, the subject being treated for drug induced liver injury has been diagnosed with an additional pathology. In some embodiments the subject has been diagnosed with alcoholic liver disease (ALD). In some embodiments the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD). In some embodiments the non-alcoholic fatty liver disease (NAFLD) is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). In some embodiments, the subject has been diagnosed with insulin resistance, obesity, and/or other metabolic syndromes. In some embodiments, the subject has been diagnosed with hepatitis. In some embodiments, the subject has been diagnosed with hepatic cirrhosis.

[0061] In some embodiments, the drug induced liver injury, for example steatohepatitis, exacerbates a pre-existing liver disease. In some embodiments, the pre-existing liver disease is alcoholic liver disease (ALD). In some embodiments, the pre-existing liver disease is non alcoholic fatty liver disease (NAFLD). In some embodiments, the pre-existing liver disease is non-alcoholic fatty liver (NAFL). In some embodiments, the pre-existing liver disease is non alcoholic steatohepatitis (NASH). In some embodiments, the pre-existing liver disease is insulin resistance, obesity, and/or other metabolic syndromes. In some embodiments, the pre-existing liver disease is hepatitis. In some embodiments, the pre-existing liver disease is hepatic cirrhosis.

Alcoholic Liver Disease (ALD)

[0062] ALD also called alcohol -related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis. It is the major cause of liver disease in Western countries. Although steatosis (fatty liver) will develop in any individual who consumes a large quantity of alcoholic beverages over a long period of time, this process is transient and reversible. More than 90% of all heavy drinkers develop fatty liver whilst about 25% develop the more severe alcoholic hepatitis, and 15% cirrhosis.

Non-alcoholic Fatty Liver Disease (NAFLD)

[0063] Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of phenotypes ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Obesity, insulin resistance, and the resulting metabolic syndrome has led to an increased prevalence of non-alcoholic fatty liver disease. This has been estimated to be present in more than 20% of patients planned for hepatectomy. Steatotic liver is more vulnerable to injury from general anesthesia and ischemia/reperfusion. Protective mechanisms against oxidative stress are significantly impaired in steatosis, and impaired energy homeostasis further sensitizes steatotic livers to surgical stress. Regeneration is delayed in steatotic livers, with a resulting prolongation of liver dysfunction. Non-alcoholic steatohepatitis (NASH)

[0064] NASH is a clinical and histological subset of NAFLD that is associated with increased all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular mortality, and increased incidence of both liver-related and non-liver-related cancers. NASH is diagnosed clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning of liver hepatocytes, often with varying degrees of fibrosis. NASH progresses with increasing degrees of fibrosis, with cirrhosis developing in a subset of patients, with the most common complication of cirrhosis being hepatocellular carcinoma. Metabolic perturbations, including insulin resistance, impaired glycemic control, and altered lipid metabolism, have been hypothesized to contribute to the molecular pathogenesis of NAFLD and NASH.

Hepatic cirrhosis

[0065] Hepatic cirrhosis is a disease in which healthy liver tissue is replaced with scar tissue. The scar tissue blocks the blood flow through the liver and slows the liver’s ability to process nutrients, hormones, drugs, and natural toxins. It usually takes months or even years for the scar tissue to build and eventually develop cirrhosis. NAFLD, ALD, or viral infections of the liver all can cause cirrhosis. In addition, anything, such as certain diseases or conditions, that damages the liver can cause cirrhosis, including cystic fibrosis, glycogen storage diseases, alpha- 1 antitrypsin deficiency, or autoimmune diseases of the liver.

Hepatitis

[0066] Hepatitis is inflammation of the liver tissue. Some people with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

[0067] Hepatitis is most commonly caused by the viruses hepatitis A, B, C, D, and E. Other causes include heavy alcohol use, certain medications, toxins, other infections, autoimmune diseases, and non-alcoholic steatohepatitis (NASH). Hepatitis A and E are mainly spread by contaminated food and water. Hepatitis B is mainly sexually transmitted, but may also be passed from mother to baby during pregnancy or childbirth and spread through infected blood. Hepatitis C is commonly spread through infected blood such as may occur during needle sharing by intravenous drug users. Hepatitis D can only infect people already infected with hepatitis B.

HSD17B13 in the liver physiology and pathophysiology

[0068] 17P-Hydroxysteroid dehydrogenases (HSD17Bs) comprise a large family of 15 members that are mainly involved in sex hormone metabolism. HSD17Bs are a group of enzymes catalyzing the conversion between 17-keto- and 17-hydroxysteroids. Most members of this family participate in the regulation of biological activity of sex hormones, including HSD17B1, HSD17B2, HSD17B3, HSD17B5 and HSD17B6. Other members are also involved in fatty acid metabolism, cholesterol biosynthesis, and bile acid production in vivo. HSD17B13 is identified as a new lipid droplet (LD)-associated protein and its expression is mainly restricted to the liver. Actually, HSD17B13 is among one of the most abundantly expressed hepatic LD-associated proteins Further, HSD17B13 is shown to locate on the surface of liver lipid droplets and its expression is markedly upregulated in the livers of patients and mice with NAFLD. A tissue distribution study demonstrated that HSD17B13 is also highly abundant in mouse liver, with very low levels in ovary, kidney, brain, lung, skeletal muscle, testis, further suggesting its key role in liver physiology.

[0069] Human HSD17B13 gene is located at chromosome 4q22.1 and its protein sequence shares a high degree of homology (78%) with HSD17B11, which is also mapped to the same chromosome. Similar to other 17BHSD members, HSD17B13 contains two conserved motifs, with one TGXGXXXG motif related to NAD(P)(H) binding and one YXXXK motif important for its catalytic activity.

[0070] HSD17B13 expression is related to metabolic nuclear receptors (NRs). Cellular lipid homeostasis is controlled by metabolic nuclear receptors (NRs) including liver X receptors (LXRs), FXR, PPARs and transcription factors such as sterol regulatory-element binding proteins (SREBPs). LXRs, including LXRa (NR1H3) and LXRP (NR1H2), are members of the NR superfamily and are key regulators in both cholesterol and fatty acid metabolism. LXRs can be activated by naturally produced oxysterols and synthetic compounds such as T0901317 and GW3965. T0901317 induces hepatic steatosis via activating LXRs. LXRa and SREBP-lc have been described as major contributors in NAFLD. Gene profiling analysis revealed that LXR activation may induce expression of several members of the HSD17B family, including HSD17B2, HSD17B5, and HSD17Bll. Further, the LXR agonist T0901317 significantly induces HSD17B13 expression at both mRNA and protein levels in mouse liver. The induction of HSD17B13 expression by T0901317 was abolished in LXRa-/- mice but not in LXRp-/- mice, suggesting LXRa plays an important role in HSD17B13 gene transcription. In addition, LXRa-induced HSD17B13 expression is markedly attenuated in SREBP-lc knock out mice indicating that LXRa upregulates HSD17B13 expression in an SREBP-lc-dependent manner. Bioinformatical analysis further reveals a putative SREBP-1 response element (SRE) in the promoter region of HSD17B13 gene, which was confirmed to be functional by a luciferase reporter assay.

[0071] Moreover, possible upregulation of NF-E2 p45 -related factor 2 (NRF2, encoded by NFE2L2) through inhibiting HSD17B13 expression may lead to decreased sensitivity to NASH. NRF2, the master regulator of cellular redox homeostasis, when activated can ameliorate steatosis, inflammation and fibrosis in experimental models of steatohepatitis. The NRF2 agonist TBE-31 has been shown to ameliorate NASH in a mouse model. HSD17B13 catalyzes the oxidation of estradiol and retinol. Estradiol is an agonist of estrogen receptors (ER, ERR). The oxidized product of retinol, retinoic acid is an agonist for the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Nuclear receptors ER, ERR, RAR and RXR negatively regulate cellular antioxidant responses through inhibition of NRF2, the master regulator of cellular redox homeostasis. Complex formation between nuclear receptors and NRF2 block binding of NRF2 to antioxidant response element (ARE) enhancers preventing NRF2 transactivation of a battery of genes involved in antioxidant responses. Decreased cellular retinoic acid pools induced by HSD17B13 inhibition may likely lead to NRF2 activation, decreasing fibrosis stimulated by retinoic acid-stimulated stellate cells. [0072] In protecting or treating a liver disease induced by chemotherapy (e.g., tamoxifen and/or toremifene), substrates, such as estradiol, retinol, or fatty acids, may compete with HSD17B13 inhibitors in interacting with HSD17B13 in many signaling pathways described herein. In some embodiments, HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than a retinol’s affinity to said HSD17B13 protein. In some embodiments, a HSD17B13 protein may comprise enzymatic activity, which may comprise retinol dehydrogenase activity. In some embodiments, HSD17B13 inhibitors are configured to decrease HSD17B13’s enzymatic activity by at least 2%, 4%, 6%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some embodiments, HSD17B13 inhibitors are configured to decrease HSD17B13’s enzymatic activity by at most 99%, 98%, 96%, 94%, 92%, 90%, 88%, 86%, 84%, 82%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 8%, or 6%. In some embodiments, HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as retinol. In some embodiments, HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than a fatty acid’s affinity to said HSD17B13 protein. In some embodiments, HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as fatty acid. In some embodiments, HSD17B13 inhibitors comprises a higher affinity to said HSD17B13 protein than an estradiol’s affinity to said HSD17B13 protein. In some embodiments, HSD17B13 inhibitors comprises about the same affinity to said HSD17B13 protein as estradiol.

[0073] HSD17B13 could also have potential as a biomarker of advanced liver disease, such NASH and liver cancer.

[0074] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

HSD17B13 inhibitors

[0075] In certain embodiments, HSD17B13 inhibitors comprise a nucleic acid molecule that is configured to cause genetic perturbation of HSD17B13 gene resulting in reduced RNA and/or protein expression of HSD17B13. The nucleic acid molecule may comprise genomic DNA, mRNA, or cDNA. [0076] In some embodiments, the HSD17B13 inhibitor is a small molecule compound. In some embodiments, the HSD17B13 inhibitor

[0077] In some embodiments, the HSD17B13 inhibitor is an RNAi. In some embodiments, the HSD17B13 inhibitor is ARO-HSD.

Examples

Example 1: HSD17B13 Assay with Estradiol Substrate:

[0078] The LC-MS/MS based Estradiol (E2) turnover assay monitors the production of estrone (El) by the action of HSD17B13 in the presence of the co-factor NAD+. The assays were performed in 96-well plates (Eppendorf deep well Plate 96/500) in an 80 mΐ reaction volume containing the following reagents (final concentrations): 4 mM Estradiol (Cayman; #10006315); 6 mMNAD⁺ (Sigma; #N0623); 30 nM HSD17B13 enzyme (in-house E. coli expressed His- tagged, purified, soluble protein); 1 M potassium phosphate buffer pH 7.4, and 0.5% DMSO. Reactions proceeded for 2 hours at 26.5°C. Estradiol conversion to Estrone was quantitated by LC-MS/MS based analyte detection, using LCMS grade reagents, as follows:

[0079] Reactions were stopped by the addition of two volumes of Acetonitrile (MeCN; LCMS grade; CAS# 75/05/8) containing deuterated estrone (D4-E1) as an internal standard (Clear Synth; #CS-T-54273; 500 ng/mL final concentration). Samples were applied to pre-prepared Bond Elut-C18 extraction cartridges (3 mL; Agilent; #12102028). The cartridges were washed and eluted in MeCN. Eluates were dried under nitrogen and resuspended in 60% methanol (LCMS grade Methanol; CAS# 67/56/1) before submission for analysis. Standard curves for E2 and El were included for quantification.

[0080]Liquid chromatography/mass spectrometry was performed on an XBridge BEH C18 column (Waters; #186003033) using 0.1% Diethyl Amine (DEA) in MeCN (mobile phase A; DEA CAS# 109-89-7), and 0.1% Diethyl Amine in milli-Q water (mobile phase B), in a 3 min gradient completing at 25% B. Analytes were detected in negative mode using MRM analysis, with E2 having an RT of 1.85 min and El having an RT of 2 min. Activity of the enzyme in the absence of NAD⁺ (negative control) was subtracted from complete reaction samples to determine substrate-dependent production of Estrone. Enzyme activity in the presence of inhibitor compounds was expressed as a percentage of the uninhibited enzyme activity, and plotted versus inhibitor concentration (ten concentrations, ranging from 30 mM - 1.5 nM). IC50 values were calculated using non-linear regression and a four-parameter logistic model on GraphPad Prism software (GraphPad Software, La Jolla, CA). IC50 values were converted into Ki values using the equation:

Ki = IC50/([S]/Km + 1) where [S] is the substrate concentration and Km is the Michaelis constant for the substrate.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating, preventing, or delaying drug induced liver injury (DILI) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

2. The method of claim 1, wherein the drug induced liver injury is caused by a cancer drug.

3. The method of claim 2, wherein the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.

4. The method of claim 2 or 3, wherein the cancer drug is tamoxifen.

5. The method of claim 1, wherein the drug induced liver injury is caused by a cardiovascular drug.

6 The method of claim 5, wherein the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.

7. The method of claim 1, wherein the drug induced liver injury is caused by a psychiatric drug.

8 The method of claim 7, wherein the psychiatric drug is amitriptyline, clozapine, or any combination thereof.

9. The method of claim 1, wherein the drug induced liver injury is caused by a nonsteroidal anti-inflammatory drugs (NSAID).

10. The method of claim 9, wherein the NSAID is pirprofen.

11. The method of any one of claims 1-10, wherein the drug induced liver injury is drug induced steatosis (DIS).

12. The method of any one of claims 1-10, wherein the drug induced liver injury is drug induced steatohepatitis (DISH).

13. The method of any one of claims 1-12, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

14. The method of any one of claims 1-12, wherein the subject has been diagnosed with non alcoholic fatty liver disease (NAFLD).

15. The method of claim 14, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

16. The method of any one of claims 1-15, wherein the HSD17B13 inhibitor is a small molecule compound.

17. The method of any one of claims 1-15, wherein the HSD17B13 inhibitor is an RNAi.

18. The method of any one of claims 1-17, wherein the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.

19. The method of any one of claims 1-17, wherein the HSD17B13 inhibitor and the drug are administered to the subject sequentially.

20. The method of any one of claims 1-17, wherein the HSD17B13 inhibitor is administered once the drug has been discontinued.

21. A method of treating drug induced steatohepatitis (DISH) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B 13) inhibitor to the subject.

22. The method of claim 21, wherein the drug induced steatohepatitis is caused by a cancer drug.

23. The method of claim 22, wherein the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.

24. The method of claim 22 or 23, wherein the cancer drug is tamoxifen.

25. The method of claim 21, wherein the drug induced steatohepatitis is caused by a cardiovascular drug.

26. The method of claim 25, wherein the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.

27. The method of claim 21, wherein the drug induced steatohepatitis is caused by a psychiatric drug.

28. The method of claim 27, wherein the psychiatric drug is amitriptyline, clozapine, or any combination thereof.

29. The method of claim 21, wherein the drug induced steatohepatitis is caused by a nonsteroidal anti-inflammatory drugs (NSAID).

30. The method of claim 29, wherein the NSAID is pirprofen.

31. The method of any one of claims 21-30, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

32. The method of any one of claims 21-30, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

33. The method of claim 32, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

34. The method of any one of claims 21-33, wherein the HSD17B13 inhibitor is a small molecule compound.

35. The method of any one of claims 21-33, wherein the HSD17B13 inhibitor is an RNAi.

36. The method of any one of claims 21-35, wherein the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.

37. The method of any one of claims 21-35, wherein the HSD17B13 inhibitor and the drug are administered to the subject sequentially.

38. The method of any one of claims 21-35, wherein the HSD17B13 inhibitor is administered once the drug has been discontinued.

39. A method of treating drug induced steatohepatitis (DISH) caused by a cancer drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

40. The method of claim 39, wherein the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.

41. The method of claim 39 or 40, wherein the cancer drug is tamoxifen.

42. The method of any one of claims 39-41, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

43. The method of any one of claims 39-41, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

44. The method of claim 43, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

45. The method of any one of claims 39-44, wherein the HSD17B13 inhibitor is a small molecule compound.

46. The method of any one of claims 39-44, wherein the HSD17B13 inhibitor is an RNAi.

47. The method of any one of claims 39-46, wherein the HSD17B13 inhibitor and the cancer drug are administered to the subject simultaneously.

48. The method of any one of claims 39-46, wherein the HSD17B13 inhibitor and the cancer drug are administered to the subject sequentially.

49. The method of any one of claims 39-46, wherein the HSD17B13 inhibitor is administered once the cancer drug has been discontinued.

50. A method of treating drug induced steatohepatitis (DISH) caused by a cardiovascular drug in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxy steroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

51. The method of claim 50, wherein the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.

52. The method of claim 50, wherein the cardiovascular drug is amiodarone.

53. The method of any one of claims 50-52, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

54. The method of any one of claims 50-52, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

55. The method of claim 54, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

56. The method of any one of claims 50-55, wherein the HSD17B13 inhibitor is a small molecule compound.

57. The method of any one of claims 50-55, wherein the HSD17B13 inhibitor is an RNAi.

58. The method of any one of claims 50-57, wherein the HSD17B13 inhibitor and the drug are administered to the subject simultaneously.

59. The method of any one of claims 50-57, wherein the HSD17B13 inhibitor and the drug are administered to the subject sequentially.

60. The method of any one of claims 50-57, wherein the HSD17B13 inhibitor is administered once the drug has been discontinued.

61. A method of treating drug induced steatohepatitis (DISH) caused by a tamoxifen in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

62. The method of claim 61, wherein tamoxifen is administered to treat breast cancer.

63. The method of claim 61, wherein tamoxifen is administered to prevent contralateral breast cancer.

64. The method of any one of claims 61-63, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

65. The method of any one of claims 61-63, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

66. The method of claim 65, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

67. The method of any one of claims 61-66, wherein the HSD17B13 inhibitor is a small molecule compound.

68. The method of any one of claims 61-66, wherein the HSD17B13 inhibitor is an RNAi.

69. The method of any one of claims 61-68, wherein the HSD17B13 inhibitor and tamoxifen are administered to the subject simultaneously.

70. The method of any one of claims 61-68, wherein the HSD17B13 inhibitor and tamoxifen are administered to the subject sequentially.

71. The method of any one of claims 61-68, wherein the HSD17B13 inhibitor is administered once tamoxifen has been discontinued.

72. A method of treating drug induced steatohepatitis (DISH) in a subject that has undergone treatment for a cancer comprising breast cancer, ovarian cancer, non-small cell lung cancer, lung cancer, head cancer, neck cancer, and colon cancer, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

73. The method of claim 72, wherein the cancer is breast cancer.

74. The method of claim 72, wherein the cancer is ovarian cancer.

75. The method of claim 72, wherein the cancer is non-small cell lung cancer.

76. The method of claim 72, wherein the cancer is lung cancer.

77. The method of claim 72, wherein the cancer is head and neck cancer.

78. The method of claim 72, wherein the cancer is colon cancer.

79. The method of any one of claims 72-78, wherein the cancer has been treated with tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.

80. The method of any one of claims 72-79, wherein the cancer has been treated with tamoxifen.

81. The method of any one of claims 72-80, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

82. The method of any one of claims 72-81, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

83. The method of claim 82, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

84. The method of any one of claims 72-83, wherein the HSD17B13 inhibitor is a small molecule compound.

85. The method of any one of claims 72-83, wherein the HSD17B13 inhibitor is an RNAi.

86. The method of any one of claims 72-85, wherein the HSD17B13 inhibitor and the cancer treatment are administered to the subject simultaneously.

87. The method of any one of claims 72-85, wherein the HSD17B13 inhibitor and the cancer treatment are administered to the subject sequentially.

88. The method of any one of claims 72-85, wherein the HSD17B13 inhibitor is administered once the cancer treatment has been discontinued.

89. A method of treating drug induced steatohepatitis (DISH) caused by a selective estrogen receptor modulator (SERM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

90. The method of claim 89, wherein the SERM is tamoxifen or toremifene.

91. The method of claim 89 or 88, wherein the SERM is tamoxifen.

92. The method of any one of claims 89-91, wherein the SERM is administered to treat breast cancer.

93. The method of any one of claims 89-91, wherein the SERM is administered to prevent contralateral breast cancer.

94. The method of any one of claims 89-93, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

95. The method of any one of claims 89-93, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

96. The method of claim 95, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

97. The method of any one of claims 89-96, wherein the HSD17B13 inhibitor is a small molecule compound.

98. The method of any one of claims 89-96, wherein the HSD17B13 inhibitor is an RNAi.

99. The method of any one of claims 89-98, wherein the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously.

100. The method of any one of claims 89-98, wherein the HSD17B13 inhibitor and the SERM are administered to the subject sequentially.

101. The method of any one of claims 89-98, wherein the HSD17B13 inhibitor is administered once the SERM has been discontinued.

102. A method of treating drug induced steatohepatitis (DISH) caused by an antifolate in a subject in need thereof, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

103. The method of claim 102, wherein the antifolate is methotrexate.

104. The method of claim 102 or 103, wherein the antifolate is administered to treat cancer.

105. The method of claim 102 or 103, wherein the antifolate is administered to treat rheumatoid arthritis.

106. The method of any one of claims 102-105, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

107. The method of any one of claims 102-105, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

108. The method of claim 107, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

109. The method of any one of claims 102-108, wherein the HSD17B13 inhibitor is a small molecule compound.

110. The method of any one of claims 102-109, wherein the HSD17B13 inhibitor is an RNAi.

111. The method of any one of claims 102-110, wherein the HSD17B13 inhibitor and the SERM are administered to the subject simultaneously.

112. The method of any one of claims 102-110, wherein the HSD17B13 inhibitor and the SERM are administered to the subject sequentially.

113. The method of any one of claims 102-110, wherein the HSD17B13 inhibitor is administered once the SERM has been discontinued.

114. A method of preventing a decrease in hepatocyte triglyceride secretion in a subject that has been administered or is being administered an additional therapeutic agent, the method comprising administering a therapeutically effective amount of a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor to the subject.

115. The method of claim 114, wherein the additional therapeutic agent is a cancer drug.

116. The method of claim 115, wherein the cancer drug is tamoxifen, toremifene, irinotecan, methotrexate, fluorouracil (5-FU), or any combination thereof.

117. The method of claim 115 or 116, wherein the cancer drug is tamoxifen.

118. The method of claim 114, wherein the additional therapeutic agent is a cardiovascular drug.

119. The method of claim 118, wherein the cardiovascular drug is amiodarone, perhexiline, propranolol, or any combination thereof.

120. The method of claim 115, wherein the additional therapeutic agent is a psychiatric drug.

121. The method of claim 120, wherein the psychiatric drug is amitriptyline, clozapine, or any combination thereof.

122. The method of claim 115, wherein the additional therapeutic agent is a nonsteroidal anti inflammatory drugs (NS AID).

123. The method of claim 122, wherein the NSAID is pirprofen.

124. The method of any one of claims 114-123, wherein the subject has been diagnosed with alcoholic liver disease (ALD).

125. The method of any one of claims 114-123, wherein the subject has been diagnosed with non-alcoholic fatty liver disease (NAFLD).

126. The method of claim 125, wherein the non-alcoholic fatty liver disease (NAFLD) is non alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH).

127. The method of any one of claims 114-126, wherein the HSD17B13 inhibitor is a small molecule compound.

128. The method of any one of claims 114-126, wherein the HSD17B13 inhibitor is an RNAi.

129. The method of any one of claims 114-128, wherein the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject simultaneously.

130. The method of any one of claims 114-128, wherein the HSD17B13 inhibitor and the additional therapeutic agent are administered to the subject sequentially.

131. The method of any one of claims 114-128, wherein the HSD17B 13 inhibitor is administered once the additional therapeutic agent has been discontinued.

132. The method of any of one of claims 1-131, further comprising reducing liver triglyceride content (TG) in the subject.

133. The method of any of one of claims 1-132, further comprising reducing plasma alanine aminotransferase (ATL) levels in the subject.

134. The method of any of one of claims 1-133, further comprising reducing plasma aspartate aminotransferase (AST) levels in the subject.

135. The method of any of one of claims 1-134, further comprising reducing plasma adipose differentiation-related protein (Adrp) levels in the subject.

136. The method of any of one of claims 1-135, further comprising reversing insulin resistance in the subject.

137. The method of any of one of claims 1-136, further comprising reducing expression levels of a plurality of hepatic lipogenic genes in the subject.

138. The method of claim 137, wherein the plurality of hepatic lipogenic genes comprises at least one gene selected from the group consisting of Srebp-1, Srebfl, Mlxipl, Xbpls, and NR1H3.

139. The method of any of one of claims 1-138, further comprising reducing expression levels of a plurality of hepatic lipid synthesis enzymes in the subject.

140. The method of claim 139, wherein the plurality of hepatic lipid synthesis enzymes comprises at least one enzyme selected from the group consisting of acetyl-CoA carboxylase alpha (Acaca), ATP citrate lyase (Acly), fatty acid synthase (Fasn), stearoyl- CoA desaturase-1 (Scdl), triglyceride synthesis enzymes diacylglycerol acyltransferase- 2 (Dgat2), lipin-1, and mitochondrial glycerol-3 -phosphate acetyltransferase (Mgpat).

141. The method of any of one of claims 1-140, further comprising increasing expression levels of a plurality of hepatic fatty acid oxidation proteins in the subject.

142. The method of claim 141, wherein the plurality of hepatic fatty acid oxidation proteins comprises at least one protein selected from the group consisting of acetyl-CoA oxidase (Acox2), carboxylesterase lg (Ceslg), and acetyl-CoA thioesterase 7 (Acot7), proliferator-activated receptor a (PPara), carnitine palmitoyl transferase la (Cptla), and short-chain acyl-CoA dehydrogenase (Scad).

143. The method of any of one of claims 1-142, further comprising increasing expression levels of a plurality of hepatic lipoprotein assembly genes in the subject.

144. The method of any of one of claims 1-143, further comprising reducing hepatic inflammation, apoptosis, or fibrosis in the subject.

145. The method of any of one of claims 1-144, further comprising reducing hepatocellular ballooning or Mallory -Denk Bodies (MDBs) in the subject.

146. The method of any of one of claims 1-145, further comprising reducing oxidative stress in the subject.

147. The method of any of one of claims 1-146, wherein the subject is a mammal.

148. The method of claim 147, wherein the subject is a human.