IGF2BP1 orchestrates glycolytic reprogramming via HK2 to accelerate hepatocellular carcinoma malignancy.

Dysregulated glucose metabolism is a hallmark of hepatocellular carcinoma (HCC), yet the upstream regulators driving this metabolic reprogramming remain incompletely understood. In this study, insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was identified as a critical oncogenic driver in HCC. Clinically, IGF2BP1 is markedly overexpressed in HCC tissues and cell lines, with expression levels correlating strongly with tumor aggressiveness. Functionally, silencing IGF2BP1 significantly attenuated HCC cell proliferation, migration, and invasion, concomitant with a profound suppression of glycolytic flux. Mechanistically, we demonstrate that IGF2BP1 directly binds to and stabilizes HK2 mRNA, thereby upregulating Hexokinase 2 (HK2) protein expression. This stabilization triggers a metabolic cascade characterized by increased glucose uptake, lactate production, pyruvate accumulation, and elevated lactate dehydrogenase A (LDHA) levels. Crucially, HK2 knockdown completely abrogated the pro-glycolytic and pro-tumorigenic effects induced by IGF2BP1, confirming HK2 as a critical downstream effector. In vivo xenograft models further corroborated these findings, showing that IGF2BP1 depletion drastically inhibited tumor growth while downregulating the HK2/LDHA axis and reducing pyruvate levels. Collectively, our study elucidates a novel IGF2BP1/HK2 axis that drives HCC malignancy via glycolytic reprogramming, highlighting IGF2BP1 as a promising prognostic biomarker and therapeutic target.