Metformin counteracts lipid accumulation and cell proliferation in hepatocellular carcinoma via regulating METTL3-mediated m6A methylation
Abstract
Metformin, a first-line antidiabetic drug, has demonstrated anticancer potential in various malignancies, yet its precise mechanisms in hepatocellular carcinoma (HCC) remain incompletely defined. Here, we show that metformin inhibits lipid accumulation and proliferation in HCC cells through modulation of N6-methyladenosine (m6A) RNA methylation. Treatment of HepG2 and Huh7 cells with metformin significantly reduced intracellular triglyceride and cholesterol levels, concomitant with decreased lipid droplet accumulation and impaired cell proliferation. Mechanistically, metformin lowered global m6A methylation by downregulating the m6A methyltransferase Methyltransferase-like 3 (METTL3), while upregulating the demethylase Fat mass and obesity-associated protein (FTO). Functional assays revealed that METTL3 overexpression restored lipid accumulation and proliferation in metformin-treated cells, whereas METTL3 knockdown phenocopied the lipid-lowering and anti-proliferative effects of metformin. Further analyses identified the METTL3/ACC1/FASN axis as a critical downstream pathway, with metformin suppressing m6A modification and expression of Fatty acid synthase (FASN) and Acetyl-CoA carboxylase 1 (ACC1) transcripts - effects reversed by METTL3 overexpression. These findings establish METTL3 as a central mediator of metformin's metabolic and antiproliferative activities in HCC, uncovering a previously unappreciated epitranscriptomic mechanism by which metformin impedes tumor…
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