ANXA4 (annexin A4) is a calcium/phospholipid-binding protein that functions as a membrane regulator involved in exocytosis and vesicle trafficking. 1 The protein modulates membrane permeability and participates in cellular growth and apoptosis through calcium-dependent mechanisms. 1 In viral infection, ANXA4 acts as a protective factor during hepatitis B virus (HBV) infection by restricting viral replication. Mechanistically, ANXA4 inhibits autophagic degradation of MCM2 (minichromosome maintenance complex component 2), thereby limiting HBV replication and liver injury. 2 Importantly, elevated ANXA4 levels (>8 ng/ml) correlate with enhanced sensitivity to interferon therapy in chr2 hepatitis B patients. 2 In cancer, ANXA4 exhibits context-dependent roles. It promotes progression and chemoresistance in multiple epithelial cancers including colorectal, gastric, lung, breast, ovarian, and renal cancers through nuclear translocation and NF-κB p50 pathway activation. 3 4 In ovarian clear cell carcinoma, ANXA4 interacts with NF-κB p50 to promote cell proliferation and inhibit apoptosis via Cyclin D1 and Bcl-2 upregulation. 4 Notably, ANXA4 functions as a tumor suppressor in prostate cancer. 3 In preeclampsia, reduced ANXA4 expression correlates with inadequate trophoblast invasion; ANXA4 overexpression promotes invasion via the PI3K/Akt/eNOS pathway. 5 Genetically, ANXA4 has been identified as a locus associated with type 2 diabetes susceptibility in Hispanic/Latino populations. 6