Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited therapeutic options. Xiong's Shiwei Wendan Decoction (XSWD) is a traditional Chinese formula that has shown clinical benefits in MASLD, but its bioactive constituents and underlying mechanisms remain poorly characterized. In this study, an integrated approach combining UHPLC-Q-TOF/MS-based serum pharmacochemistry with multi-omics was employed to elucidate the chemical basis and mechanisms of XSWD in treating MASLD. The bioactive constituents of XSWD-containing serum were characterized using UHPLC-Q-TOF/MS, annotating 34 major compounds including flavonoids, triterpenoids, and phenolic acids. To evaluate therapeutic efficacy, MASLD was induced in both C57BL/6 J and ApoE-/- mice via a high-fat diet, followed by a 6-week XSWD intervention. XSWD significantly attenuated hepatic steatosis, improved serum lipid profiles, and restored liver function. Furthermore, XSWD mitigated hepatic inflammation and oxidative stress by suppressing macrophage infiltration and pro-inflammatory cytokine expression. To explore the underlying molecular mechanisms, integrated transcriptomic and proteomic analyses were performed on liver tissues. The multi-omics profiling revealed that XSWD-mediated hepatoprotection was primarily driven by the inhibition of de novo lipogenesis. Specifically, XSWD downregulated the pivotal transcription factor SREBP-1c and its downstream lipogenic targets, including FASN, SCD1, and ACLY, which was further validated by RT-qPCR and Western blot. This study integrates UHPLC-Q-TOF/MS-based profiling with multi-omics and in vivo validation to elucidate the potential mechanisms of XSWD in the treatment of MASLD.