The peroxisome proliferator-activated receptor α/β/γ agonist NCPC-626 from microbial metabolites alleviates metabolic dysfunction-associated steatohepatitis in mice.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by steatosis, inflammatory responses, and fibrosis. Peroxisome proliferator-activated receptors (PPARs), master regulators of glucolipid homeostasis and inflammatory pathways, have emerged as promising therapeutic targets for MASH. PPAR agonists have demonstrated therapeutic potential in MASH by ameliorating hepatic lipid deposition, normalizing dyslipidemia, enhancing insulin sensitivity, and suppressing proinflammatory signaling. In this study, we reported that NCPC-626, a natural fungal metabolite, was discovered as a novel potent pan-PPAR agonist through high-throughput screening. In an in vitro model of MASH, NCPC-626 inhibited lipid accumulation, fibrosis, and inflammation. Moreover, NCPC-626 treatment reduced body weight, liver triglyceride levels, and improved glucose tolerance in db/db mice by regulating glucolipid metabolism. Additionally, NCPC-626 exhibited preventive and therapeutic effects against fibrosis in a CCl4-induced fibrosis model and ameliorated MASH progression in a diet-induced model. This study highlights NCPC-626 as a pan-PPAR agonist with a novel chemical scaffold for MASH treatment. SIGNIFICANCE STATEMENT: This study identifies a novel structural compound, NCPC-626, demonstrating specific and balanced activation of peroxisome proliferator-activated receptors. NCPC-626 demonstrates therapeutic efficacy against metabolic dysfunction-associated steatohepatitis in experimental models.