ANXA2 is a multifunctional calcium-dependent phospholipid-binding protein with critical roles in cellular mechanotransduction, autophagy, and disease pathogenesis. Mechanistically, ANXA2 functions through phosphorylation-dependent conformational changes at tyrosine 24 (Y24), which regulates its interaction with various binding partners including integrin α5β1, USP4, and ATG7. In vascular homeostasis, ANXA2 serves as a carrier protein coupling integrin α5 to lipid rafts during oscillatory shear stress, promoting endothelial activation 1. In cancer progression, ANXA2 promotes glioblastoma stem cell maintenance and radioresistance through USP4-mediated stabilization and STAT3 activation 2, enhances triple-negative breast cancer aggressiveness by upregulating ATG7-mediated autophagy via HSF1 phosphorylation 3, and supports bladder cancer malignancy through Y24 phosphorylation promoted by m7G-modified tsRNA 4. ANXA2 is also significantly overexpressed in Alzheimer's disease where it colocalizes with microglial cells and amyloid-β plaques, potentially disrupting synaptic homeostasis 5. Additionally, ANXA2 mediates microplastic endocytosis in breast cancer cells, triggering mitochondrial damage and mitophagy 6. In non-alcoholic fatty liver disease, ANXA2 promotes ferroptosis and represents a diagnostic biomarker 7. These diverse functions establish ANXA2 as a central hub in disease pathogenesis across multiple organ systems.