Yinqi Tiaozhi Decoction ameliorates hepatic steatosis in metabolic dysfunction-associated fatty liver disease by regulating the miR-122-5p/FOXO3 axis to modulate lipid metabolism and oxidative stress

Abstract

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) lacks targeted pharmacotherapies. Objective: This study investigates whether Yinqi Tiaozhi Decoction (YQTZD) alleviates MAFLD via the miR-122-5p/forkhead box O3 (FOXO3) axis. Methods: MAFLD was modeled using oleic acid–treated AML12 cells and rats fed a choline-deficient high-fat diet. The effects of YQTZD or YQTZD-containing serum on lipid accumulation, oxidative stress, inflammation, glucose metabolism, and miR-122-5p/FOXO3 expression were evaluated, and the role of miR-122-5p was further examined using mimic transfection. Results: YQTZD-containing serum (YQTZD-CS) dose-dependently enhanced AML12 cell viability, reduced lipid accumulation (total cholesterol and triglycerides), and mitigated oxidative injury, as reflected by changes in superoxide dismutase, malondialdehyde, and glutathione peroxidase levels. MiR-122-5p downregulation and FOXO3 upregulation were observed alongside these protective effects, while miR-122-5p mimic transfection abolished YQTZD-CS’s protection. In choline-deficient high-fat diet-induced MAFLD rats, YQTZD improved body weight, glucose tolerance, and insulin sensitivity, while histopathological assessments confirmed marked attenuation of hepatic steatosis. It also reduced serum lipids, suppressed hepatic pro-inflammatory mediators (interleukin [IL]-6, tumor necrosis factor alpha, and IL-1β), and mitigated oxidative stress, alongside elevated glutamine synthetase activity and glutamine levels. Crucially, YQTZD consistently suppressed miR-122-5p and upregulated FOXO3 in vivo. Thus, YQTZD mitigates hepatic steatosis, oxidative damage, and inflammation in MAFLD, mechanistically linked to miR-122-5p downregulation-mediated FOXO3 upregulation. Conclusion: This study underscores the translational promise of YQTZD and provides a mechanistic foundation for its future integration into clinical management of MAFLD.