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

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. Promisingly, emerging ANXA2-targeted strategies demonstrate therapeutic potential, including exosome and microenvironment modulation, molecular targeted therapy, regulation of the ANXA2-NF-κB axis, Nanotechnology, and radionuclide theranostics. Collectively, this review establishes an integrated "etiology-mechanism-intervention" framework while providing novel molecular targets and a theoretical foundation for precision medicine approaches in HCC.