Metformin and atorvastatin ameliorate MASH via the AMPK/NF-κB pathway

Background Despite being a globally prevalent chronic liver disease, MASLD currently lacks any approved pharmacotherapy. MET and ATO individually confer benefits against MASLD, but their combined therapeutic effects have seldom been investigated. The current work aimed to verify the therapeutic benefits of their combined intervention on MASH. Methods A MASH-like mouse model was established via HFD feeding combined with CCl 4 injection, alongside an FFA-induced HepG2 steatosis model. Serum biochemical markers and inflammatory cytokines were measured, and lipid deposition was assessed by Oil Red O staining. Western blotting was performed to evaluate the expression of lipid metabolism-related proteins and AMPK/NF-κB signaling pathway components. Additionally, Compound C, a pharmacological inhibitor of AMPK, was used to verify the underlying molecular mechanism. Results Co-treatment with MET and ATO markedly alleviated FFA-induced lipid accumulation and TG/TC levels in HepG2 cells. Combination therapy in HFD/CCl 4 -induced MASH-like mice reduced body/liver weights, fasting glucose and HOMA-IR. Mechanistically, it downregulated lipogenic proteins SREBP-1 and HMGCR while upregulating fatty acid oxidation regulators CPT1A and PPARα. Additionally, it suppressed IL-6, TNF-α and IL-1β secretion via inhibiting NF-κB phosphorylation, thereby mitigating hepatic and cellular inflammation. Moreover, the combination enhanced AMPK phosphorylation, while the AMPK inhibitor Compound C largely abolished these protective effects. Conclusion These observations indicate that the combined MET and ATO treatment exerts lipid-lowering and anti-inflammatory effects possibly via the AMPK/NF-κB signaling axis.