Selective PPARα Modulator Pemafibrate Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease Through Regulation of Leptin Signaling and Remodeling of Gut Microbiota.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease worldwide, and effective pharmacological therapies remain limited. Pemafibrate (Pema), a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator (SPPARMα), has shown promising therapeutic potential in patients with MASLD and hypertriglyceridemia; however, its underlying mechanisms remain incompletely understood. Here, we investigated the therapeutic effects and molecular mechanisms of Pema using in vitro and in vivo MASLD models and evaluated its clinical relevance in patients with MASLD. In a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASLD mouse model, Pema dose-dependently ameliorated hepatic steatosis and fibrosis and significantly suppressed the hepatic expression of inflammatory and fibrogenic genes, including TLR4, TNFα, αSMA, and Col1A1. Pema also favorably altered the gut microbiota by increasing the abundance of the phylum Verrucomicrobia, suggesting modulation of the gut-liver axis. In differentiated 3T3-L1 adipocyte-like cells, Pema induced PPARα expression, inhibited insulin-mediated EGR-1 induction, and significantly reduced leptin secretion. Consistent with these findings, serum insulin and leptin levels, as well as the hepatic accumulation of both molecules, were markedly decreased in Pema-treated MASLD mice. Furthermore, in a clinical cohort of 192 patients with MASLD and hypertriglyceridemia, long-term Pema treatment significantly improved liver-related biochemical parameters, insulin resistance, surrogate markers of liver fibrosis, and serum leptin levels. Collectively, these findings demonstrate that Pema attenuates MASLD progression by suppressing leptin-mediated metabolic and inflammatory signaling while improving the gut microenvironment. These results highlight SPPARMα as a promising therapeutic strategy for MASLD and support further clinical investigation of Pema as a disease-modifying treatment targeting the gut-liver axis.