S100A6 (calcyclin) is a calcium-binding protein that functions as a critical regulator of cell proliferation, migration, and metastasis, particularly in cancer contexts. 1 Structurally, S100A6 contains two EF-hand calcium-binding domains and interacts with multiple intracellular and extracellular proteins in a calcium-dependent manner. 2 In hepatocellular carcinoma (HCC), S100A6 marks a pro-metastatic epithelial-mesenchymal transition (EMT) subtype of tumor cells that shows activation of SMAD3 and TGF-β signaling pathways. 3 S100A6 promotes lymph node metastasis through dual mechanisms: tumor cell-intrinsic effects enhancing migration and invasion, and paracrine signaling that activates the RAGE/NF-κB/VEGF-D pathway in lymphatic endothelial cells to promote lymphangiogenesis. 4 High S100A6 expression correlates with poor overall survival in pancreatic cancer and modulates the tumor immune microenvironment. 5 Beyond oncology, S100A6 regulates cytoskeleton dynamics, cell stress responses, and cell differentiation. 1 Its expression is regulated by transcription factors including c-Myc, p53, and NF-κB and is modulated by epigenetic mechanisms. 1 S100A6 serves as a biomarker for disease progression and stratification in metabolic-associated steatohepatitis (MASH). 6 The protein can be secreted and acts extracellularly through RAGE and integrin β1 signaling. 7