New drug therapies for metabolic dysfunction-associated steatohepatitis

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly increased world-wide to 30%, with increasing of type 2 diabetes (T2D) and obesity in last two decades. The spectrum of MASLD covers from simple hepatic steatosis to the progressive metabolic dysfunction-associated steatohepatitis (MASH) with or without fibrosis, cirrhosis and hepatocellular carcinoma. The MASLD symptoms include dyslipidemia, hyperglycemia, insulin resistance and obesity, the liver manifestations of metabolic syndrome. Treatment option for MASH fibrosis is limited. Since the discovery of bile acids as the endogenous ligands of farnesoid X receptor (FXR) in early 1990, bile acid and FXR based-drug therapies have been developed and tested in clinical trials for cholestatic liver diseases and MASH fibrosis. However, many of these drugs have unwanted side-effects and moderate efficacy in improving fibrosis. The US Food and Drug Administration has not approved any of bile acid- and FXR-based drugs for MASH fibrosis. Drug therapies alternative to bile acid derivatives for MASH have been in clinical trials. Recently, resmetirom, a liver-specific- and thyroid hormone receptor beta-selective agonist has been approved for MASH fibrosis. Glucagon-like peptide-1 receptor agonists also are in clinical trials for MASH. This review covers recent development of novel drug therapies for MASH fibrosis, T2D and obesity.

Keywords

Bile acids / Farnesoid X receptor (FXR) / Takeda G protein-coupled receptor 5 (TGR5) / Glucagon-like peptide-1 (GLP-1) / Metabolic dysfunction-associated steatotic liver disease (MASLD) / Metabolic dysfunction-associated steatohepatitis (MASH)

Author’s contributions

John Y. L. Chiang: Conceptualization, Writing-original draft, Writing-review & editing, Funding acquisition.

Declaration of competing interest

John Y. L. Chiang is an executive associate editor for liver research and was not involved in the editorial review or the deci-sion to publish this article. The author declares that there is no conflicts of interest.

Acknowledgements

This work was supported by National Institutes of Health (NIH) grants DK44442 and DK58379.

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