ANXA2 in hepatocellular carcinoma: orchestrating tumorigenesis, progression, and therapeutic resistance toward precision targeting

作者：Junyu Chen, Jianlin Li, Liuxin Ran, Jianbo Yang, Yang Xie · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07177-9 · 被引用次数：4 · 研究领域：Medicine

Hepatocellular carcinoma (HCC) represents a highly heterogeneous malignancy whose pathogenesis involves multiple etiological factors, including hepatitis viruses, metabolic disorders, and environmental carcinogens. Nevertheless, clinical management continues to face significant challenges due to high rates of postoperative recurrence, metastasis, and drug resistance. Emerging evidence indicates that Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, plays a pivotal role throughout HCC progression by integrating multiple oncogenic pathways. This review systematically elucidates ANXA2’s multifaceted regulatory mechanisms in HCC pathogenesis. Functioning as a critical molecular nexus, ANXA2 is dynamically modulated in its expression and activity by hepatic insults, particularly HBV/HCV infection, Alcoholic Liver Disease (ALD), Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD), and tobacco exposure, thereby bridging chronic liver injury and malignant transformation. Mechanistically, ANXA2 promotes tumor progression through multiple pathways, including ubiquitination regulation, stem cell characteristic regulation, cytoskeletal remodeling, Epithelial–Mesenchymal Transition (EMT) induction, and autophagy modulation. Furthermore, it confers chemotherapy resistance specifically through regulating apoptosis evasion, ferroptosis suppression, and autophagy homeostasis, while its effects on radiotherapy and immunotherapy responses involve distinct mechanisms...