Abstract
Background: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, and metabolic reprogramming, particularly glycolysis, plays a crucial role in its progression. Circular RNAs (circRNAs) and N6-methyladenosine (m6A) modifications have emerged as key regulators in HCC, but the role of circGDI2 and its underlying mechanisms remain unclear. Objective: This study aimed to investigate the functional role and mechanism of circGDI2 in HCC proliferation and glycolysis. Methods: The expression of circGDI2 was detected by RT-qPCR. RNase R treatment was used to verify the stability of circGDI2. Functional assays, including CCK-8, glycolysis analysis (glucose consumption, lactate production), and xenograft model, were performed to assess proliferation and glycolysis. Bioinformatics prediction, MeRIP, and luciferase reporter assays were used to explore the interaction between circGDI2, IGF2BP2, and PKM2. Results: CircGDI2 was highly expressed in HCC tissues and cells, and exhibited cytoplasm localization. Silencing circGDI2 inhibited Li-7 and Huh-7 cell proliferation and glycolysis, downregulated PKM2, and suppressed tumor growth. Mechanistically, circGDI2 regulated PKM2 through the m6A "reader" IGF2BP2, and its overexpression partially rescued the inhibitory effects of circGDI2 knockdown. Furthermore, FTO-mediated m6A modification enhanced circGDI2 stability and expression. Silencing FTO inhibited HCC cell proliferation, glycolysis, and tumor growth, and decreased the levels of circGDI2, IGF2BP2, and PKM2. Conclusions: FTO-mediated m6A modification of circGDI2 promotes HCC proliferation and glycolysis via the IGF2BP2/PKM2 axis, suggesting circGDI2 as a potential therapeutic target for HCC.