QHHP Ameliorates MASH Through Modulation of a Cyp4a32-PPARγ-CD36-Associated Lipotoxic Axis

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive stage of metabolic dysfunction-associated fatty liver disease, for which effective pharmacological therapies remain limited. Qinggan Huatan Huoxue Prescription (QHHP) has been used clinically in the management of fatty liver disease and related metabolic disorders, but its overall efficacy and underlying mechanisms remain unclear. In this study, the therapeutic effects of QHHP on MASH were evaluated through clinical observation, animal experiments, cellular studies, multi-omics analysis, and computational simulation. QHHP treatment was associated with improved liver function and selected lipid parameters in patients with MASH, attenuated steatosis, inflammation, and fibrosis in HFHC- and MCD-induced mouse models, and reduced PA/OA-induced lipid droplet accumulation in AML12 cells and PMHs. Transcriptomic and pathway analyses indicated the involvement of PPAR signaling and fatty acid metabolism-related pathways. In vivo and in vitro findings showed that QHHP intervention was accompanied by downregulation of Cyp4a32, PPARγ, and CD36. Pathway-intervention experiments further showed that siPPARγ enhanced, whereas Rosiglitazone partially reversed the inhibitory effects of QHHP on lipid droplet accumulation and related molecular expression, suggesting that PPARγ-related lipid uptake signaling participates in its anti-lipotoxic mechanism. QHHP may alleviate hepatic lipotoxic injury through multi-component regulation of a lipid metabolism-related network involving Cyp4a32, PPARγ, and CD36.