COMMD5 is a scaffold protein functioning as a component of the commander complex essential for endosomal recycling of transmembrane cargos 1. Its N-terminus binds endosomal Rab5 while its C-terminus interacts with cytoskeletal scaffolding, enabling coordination of EGFR trafficking and endosome transport along microtubules 2. COMMD5 negatively regulates cell proliferation through p21/CDKN1A transactivation via p53-independent signaling 3 and suppresses NF-κB activation. In kidney physiology, COMMD5 promotes proximal tubule epithelial cell re-differentiation and maintains tubular integrity following acute kidney injury 4. During cisplatin-induced nephrotoxicity, COMMD5 overexpression protects tubular epithelial cells by reducing reactive oxygen species, preserving mitochondrial function, and maintaining autophagy flux 4. Clinically, COMMD5 shows tumor-suppressive properties in renal cell carcinoma, with low expression correlating with tumorigenesis and poor outcomes 5. However, COMMD5 exhibits paradoxical roles in RCC metastasis, suppressing primary tumor growth while enhancing metastatic lung nodule formation and survival under hypoxia 6. Additionally, COMMD5 regulates blood pressure through endothelial nitric oxide synthase modulation, with elevated serum levels contributing to post-parathyroidectomy hypotension 7.