S100A3 is a calcium and zinc-binding protein of the EF-hand S100 family, primarily involved in epithelial differentiation and hair cuticle formation 1. The protein contains ten cysteines forming disulfide bridges and a preformed zinc-binding pocket; post-translational citrullination at arginine residues enables calcium-dependent tetramer assembly 23. S100A3 structurally expanded upon calcium/zinc binding, stabilized by citrullination 3. Clinically, S100A3 demonstrates significant oncogenic roles across multiple cancer types. Expression is elevated in hepatocellular carcinoma 4, colorectal cancer (2.4-fold increase in tumor cells) 5, and castration-resistant prostate cancer 6. In prostate cancer, S100A3 suppression reduced cell viability via apoptosis, decreased invasion through MMP-2/MMP-9 downregulation, and inhibited xenograft tumor growth 6. In intrahepatic cholangiocarcinoma, S100A3 upregulation associates with enhanced cell migration/invasion 7. Additionally, S100A3 interacts directly with retinoic acid receptor alpha (RARα) and PML-RARα, regulating their stability and ATRA-induced differentiation across breast cancer, lung cancer, and acute myeloid leukemia 8. Pharmacological inhibition via sodium cantharidinate suppressed S100A3 expression in hepatocellular and colorectal cancer cells 45, suggesting therapeutic potential as a novel cancer treatment target.