Metabolic dysfunction-associated steatohepatitis (MASH) is a primary driver of hepatocellular carcinoma (HCC), yet effective therapeutic interventions remain limited. While luteolin is known for its anti-inflammatory properties, its efficacy and underlying mechanism in the MASH-HCC transition are not fully understood. This study investigated the protective effects of luteolin against MASH-HCC and the role of the AMPK/ACC signaling pathway in this process. In vivo, a MASH-HCC mouse model was established using diethylnitrosamine (DEN) combined with a high-fat, high-cholesterol (HFHC) diet. Mice were treated with vehicle or luteolin (50 or 100 mg/kg) for 26 weeks. Progression was monitored via serum alpha-fetoprotein (AFP), histological analysis, and Western blotting. In vitro , HepG2 and Huh-7 cells were challenged with cholesterol and treated with luteolin. The AMPK inhibitor BAY-3827 was employed to verify whether the metabolic benefits of luteolin were pathway-dependent. Luteolin treatment significantly reduced tumor burden, lowered serum AFP levels, and attenuated hepatic lipid accumulation and fibrosis in MASH-HCC mice. In vitro results mirrored these findings, showing that luteolin reduced cholesterol-induced lipid loading. Mechanistically, luteolin increased the phosphorylation of AMPK and its downstream target, ACC. Furthermore, pharmacological inhibition of AMPK with BAY-3827 abolished the lipid-lowering effects of luteolin in hepatic cells, confirming that its therapeutic benefits are mediated through AMPK activation. Luteolin suppresses the progression of MASH to HCC by activating the AMPK/ACC signaling pathway and subsequently inhibiting de novo lipogenesis. These findings highlight luteolin as a promising potential therapeutic candidate for the prevention and treatment of MASH-related liver cancer. • Luteolin significantly reduces tumor burden and fibrosis in a MASH-HCC mouse model. • Luteolin attenuates hepatic lipid accumulation by inhibiting de novo lipogenesis. • The protective effects of luteolin are mediated via the AMPK/ACC signaling pathway. • Inhibition of AMPK abolishes the lipid-lowering benefits of luteolin in hepatocytes.
Shao et al. (Fri,) studied this question.