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 treat-ment 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.
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis(MASH)are based primarily on dietary restrictions and the use of existing drugs,including anti-diabetic and anti-obesity medications.Given the limited number of approved drugs specifically for MASH,recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism,inflamma-tion,fibrosis,or a combination of these processes.In this review,we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy.Particularly,we analyzed the effects of lipogenesis inhibitors,nuclear receptor agonists,glucagon-like peptide-1(GLP-1)receptor(GLP-1R)agonists,fibroblast growth factor mimetics,and combinatorial therapeutic approaches.We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.
Zhifu XieYufeng LiLong ChengYidan HuangWanglin RaoHonglu ShiJingya Li
