Isocitrate dehydrogenase 2 promotes tumor progression and glycolysis in cervical squamous cell carcinoma by activating the HIF1A signaling pathway

Isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme central to metabolic processes, has been associated with tumorigenesis in multiple cancers; however, its functional significance in cervical squamous cell carcinoma (CSCC) remains unclear. We assessed IDH2 expression in clinical CSCC samples and established cell lines. Functional analyses, including IDH2 knockdown in CaSki cells, were performed to evaluate its impact on cellular proliferation, migratory capacity, and glycolytic metabolism. To uncover the molecular mechanism, we investigated the interplay between IDH2 and hypoxia-inducible factor 1-alpha (HIF1α), along with the expression of downstream glycolytic targets such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). The in vivo role of IDH2 was further examined using xenograft models in nude mice, monitoring tumor growth and the levels of HIF1α, Ki67, and glycolytic indicators. IDH2 was markedly overexpressed in both CSCC tissues and cell lines, with elevated levels correlating with with elevated levels associated with enhanced malignant potential in functional assays. Depletion of IDH2 inhibited cell proliferation, migration, and glycolytic activity in CaSki cells. Mechanistically, IDH2 was shown to upregulate HIF1α, thereby enhancing the transcription of glycolytic enzymes HK2 and LDHA. Notably, the oncogenic and metabolic effects induced by IDH2 were reversed upon HIF1α silencing, confirming its essential mediating role. In mouse models, IDH2 knockdown significantly suppressed tumor growth and downregulated HIF1α, Ki67, and key glycolytic markers. Notably, the oncogenic and metabolic effects induced by IDH2 were reversed upon HIF1α silencing, confirming its essential mediating role. Our study identifies an IDH2-HIF1α-glycolysis signaling cascade that promotes CSCC progression. These findings establish IDH2 as a key driver of metabolic reprogramming in cervical cancer and support its potential as a target for therapeutic strategies, potentially involving the repurposing of existing IDH2 inhibitors, aimed at disrupting cancer metabolism in CSCC.