COX4I2 (cytochrome c oxidase subunit 4I2) encodes a structural subunit of cytochrome c oxidase (complex IV), the terminal enzyme of the mitochondrial electron transport chain that catalyzes oxygen reduction to water during oxidative phosphorylation 1. The protein functions in mitochondrial respiration and is subject to post-translational regulation, including deacetylation by SIRT3 to maintain mitochondrial homeostasis 2. COX4I2 expression is transcriptionally regulated by hypoxia-inducible factor 1α (HIF1A) under hypoxic conditions 3 and by EBF1 in cancer-associated fibroblasts 4. The gene exhibits tissue-specific expression patterns, with relatively high levels in pancreatic acinar cells 1. Mutations in COX4I2 cause a rare syndrome characterized by exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis, associated with reduced COX4I2 expression and impaired hypoxic response 1. In cancer contexts, COX4I2 overexpression promotes tumor progression through enhanced angiogenesis 53 and epithelial-mesenchymal transition 5. The protein serves as a biomarker for highly vascular tumors and metabolism-type pheochromocytomas 6, while also contributing to immunosuppressive tumor microenvironments in colorectal cancer 4. Mendelian randomization studies suggest protective roles against osteoarthritis 7.