COMMD3 is a scaffold protein within the commander complex that regulates endosomal recycling of transmembrane cargo proteins 1. It functions as a component of the CCC (COMMD/CCDC22/CCDC93) subcomplex and coordinates endosomal trafficking through interactions with other transport machinery 2. COMMD3 modulates sodium transport in epithelial cells by regulating apical surface expression of ENaC (epithelial sodium channel) subunits 3, affecting Na+ homeostasis and blood pressure regulation. The COMMD3/8 complex serves as a specificity adaptor that recruits GRK6 to chemoattractant receptors, regulating B cell migration and humoral immune responses 4. COMMD3 also modulates melanosomal pH during melanogenesis 5 and participates in α-granule biogenesis in platelets 2. Functionally, COMMD3 regulates lysosomal homeostasis, and loss of COMMD3 impairs lysosomal protein delivery through increased extracellular vesicle release 6. Rare COMMD gene variants are associated with increased Parkinson's disease risk, suggesting COMMD3 modulates neurodegeneration linked to lysosomal dysfunction 6. In hepatocellular carcinoma, elevated COMMD3 expression correlates with poor prognosis and supports cancer cell proliferation 7. COMMD3 is also targetable therapeutically; celastrol selectively inhibits the COMMD3/8 complex, suppressing autoimmune responses in rheumatoid arthritis models 8.