Nuclear Receptor-Targeted Therapy for Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting over 25% of the global population. Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced stage of MASLD, characterized by hepatic steatosis accompanied by inflammation, hepatocellular injury, and fibrosis. Despite its high prevalence and clinical significance, effective treatments for MASLD and MASH remain limited, largely due to the complexity of the underlying pathophysiological mechanism, which remains not yet fully understood. Nuclear receptors (NRs) are a superfamily of transcription factors and play a key role in regulating lipid metabolism, glucose homeostasis, inflammation, and fibrosis, all of which are central to MASLD progression. Consequently, NRs have emerged as promising molecular targets for MASLD treatment, and a few new NR-targeted drugs were approved recently, including thyroid hormone receptor-β (THR-β) agonist resmetirom, the dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist saroglitazar. Moreover, several NR-targeted drugs are under clinical trials. In this mini-review, we summarize the recent progress of the mechanisms of key NRs in the pathogenesis of MASLD, and discuss the advances in nuclear receptor-targeted therapy, with emphasis on THR-β, PPARs, and the non-bile acid farnesoid X receptor (FXR).