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Targeting the AMPK/ACC pathway with luteolin suppresses de novo lipogenesis and limits tumor burden in a MASH-HCC
Gaoxuan Shao1, Chenceng Sun2, Chenhao Ye3
1Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China; Shanghai Frontier Research Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, 200032, China.
Aims:
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.
Materials And Methods:
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.
Key Findings:
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.
Significance:
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.
Insights
Luteolin, a natural compound, effectively prevents the progression from metabolic dysfunction-associated steatohepatitis (MASH) to liver cancer (HCC) by activating the AMPK/ACC pathway. This mechanism reduces fat accumulation and tumor growth, offering a promising therapeutic strategy.
Area of Science:
- Hepatology and Oncology
- Molecular Biology
- Pharmacology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for hepatocellular carcinoma (HCC).
- Current therapeutic options for MASH-induced HCC are limited.
- Luteolin, known for anti-inflammatory effects, has potential but its role in MASH-HCC transition is unclear.
Purpose of the Study:
- To investigate the protective effects of luteolin against MASH progression to HCC.
- To elucidate the underlying molecular mechanisms involving the AMPK/ACC signaling pathway.
Main Methods:
- A MASH-HCC mouse model was induced using DEN and a high-fat diet, followed by luteolin treatment.
- In vitro studies used HepG2 and Huh-7 cells challenged with cholesterol and treated with luteolin.
- The role of the AMPK/ACC pathway was assessed using Western blotting and an AMPK inhibitor (BAY-3827).
Main Results:
- Luteolin significantly reduced tumor burden, serum AFP levels, and hepatic lipid accumulation and fibrosis in MASH-HCC mice.
- Luteolin decreased cholesterol-induced lipid accumulation in hepatic cells.
- Luteolin activated the AMPK/ACC pathway, and inhibiting AMPK abolished its lipid-lowering effects.
Conclusions:
- Luteolin suppresses MASH to HCC progression by activating the AMPK/ACC pathway, inhibiting de novo lipogenesis.
- Luteolin demonstrates potential as a therapeutic agent for MASH-related liver cancer.
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