Hypoxia-mediated m6A modulation in hepatocellular carcinoma: a comprehensive review

作者：Haitao Jiang, Shao Qian, Di Pan, Cancan Jin, Qinglan Pu · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07155-1 · 被引用次数：7 · 研究领域：RNA modifications and cancer、Cancer, Hypoxia, and Metabolism、Ferroptosis and cancer prognosis

Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths globally, characterised by high incidence and extremely poor prognosis. In the context of cirrhosis, the hypoxic microenvironment resulting from HCC's intricate vascular network is closely associated with the poor therapeutic outcomes of targeted and immunotherapies in advanced HCC patients. In recent years, growing evidence indicates a profound intrinsic connection between the N6-methyladenine (m6A) epigenetic modification and tumor immune evasion, metabolic reprogramming, and ferroptosis resistance. As the cross-regulatory mechanisms of hypoxia-mediated m6A are progressively elucidated, the dynamic interplay of the hypoxia-m6A axis offers novel therapeutic perspectives and targets for clinical management of HCC. This review systematically elucidates the molecular mechanisms by which hypoxia-inducible factor (HIF-1α) and key m6A-modifying enzymes (METTL3, FTO, YTHDF2) jointly regulate HCC progression within the hypoxic microenvironment. From a clinical perspective, it demonstrates the potential of the hypoxia-m6A axis as a biomarker and a novel therapeutic target for overcoming treatment resistance in HCC. It critically discusses current limitations, including inconsistent research findings, challenges in translating clinical models, and off-target risks in combination therapies. Future research should focus on developing novel controllable targeted nanomedicines and immune checkpoint i...