Sinha Rohit A
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Liver Res. 2024 Mar;8(1):34-45. doi: 10.1016/j.livres.2024.03.002.
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.
代谢功能障碍相关脂肪性肝炎（MASH）或非酒精性脂肪性肝炎（NASH）的发病代表了一个转折点，在现在称为代谢功能障碍相关脂肪性肝病（MASLD，以前称为非酒精性脂肪性肝病（NAFLD））的自然进展过程中，会导致肝损伤及随后的肝脏并发症。由于目前尚无针对MASH/NASH的药物治疗方法，因此人们竞相开发针对肝脏代谢、炎症和促纤维化事件等多个方面的药物，这些是MASH的主要驱动因素。核受体（NRs）在与亲脂性配体结合后调节基因组转录，并控制肝脏代谢和炎症的多个方面。NRs的配体可能包括激素、脂质、胆汁酸和合成配体，它们与NRs结合后可调节靶基因的转录活性。目前，NR配体是最有希望获得美国食品药品监督管理局批准作为MASH药物治疗的候选药物。本综述旨在涵盖目前对NRs的认识，包括核激素受体、非甾体激素受体、昼夜节律NRs和孤儿NRs，它们目前正处于MASH治疗的临床试验阶段，以及在临床前研究中已显示出有前景结果的NRs。
