Targeting nuclear receptors for NASH/MASH: From bench to bedside

Abstract

The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.