IGF2BP3 Orchestrates Metabolic Reprogramming via Stabilizing m6A-Modified PLK1 mRNA to Promote Hepatocellular Carcinoma Progression

Epigenetic dysregulation, particularly N6-methyladenosine (m6A) modification, drives hepatocellular carcinoma (HCC) progression, yet the oncogenic role of the m6A reader IGF2BP3 remains incompletely understood. This study aimed to elucidate the functional contributions and molecular mechanisms of IGF2BP3 in HCC. Multi-omics databases and tissue microarrays were employed to evaluate IGF2BP3 and PLK1 expression, clinicopathological associations, and prognostic value via Kaplan–Meier, Cox regression, and ROC analyses. Molecular interactions were probed by RIP, luciferase reporter, MeRIP, dot blot, and actinomycin D assays. In vitro gain/loss-of-function experiments measured glycolytic metabolites, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), mitochondrial mass/charge, ROS, and key proteins of glycolysis and oxidative phosphorylation (OXPHOS). Both IGF2BP3 and PLK1 were significantly upregulated in HCC versus adjacent non-tumor tissues, correlating positively with advanced clinical stage, higher tumor grade, and poorer overall survival. In the TCGA-LIHC discovery cohort, each showed an independent prognostic association with unfavorable outcomes after adjustment for established clinical covariates. PLK1 mRNA was validated to carry m6A modifications and directly bind IGF2BP3, an interaction abolished by cycloleucine. Functionally, IGF2BP3 upregulated m6A-modified PLK1 by enhancing its mRNA stability, leading to elevated HK2 expression, increased glucose-6-phosphate and lactate levels, and enhanced ECAR, while suppressing mitochondrial respiratory chain complexes, ROS production, and OCR. In conclusion, IGF2BP3 is overexpressed in HCC and tightly associated with aggressive clinicopathological features and adverse outcomes. Altogether, these findings suggest that IGF2BP3 may enhance the stability of the m6A-modified PLK1 transcript, orchestrating a metabolic rewiring from oxidative phosphorylation to glycolysis, revealing a potential IGF2BP3–m6A–PLK1 axis driving HCC aggressiveness and offering potential therapeutic targets for precision intervention.