UBXN6 (UBX domain protein 6) functions as a critical cofactor for VCP/p97, an AAA-ATPase that regulates protein quality control and organellar homeostasis. UBXN6 negatively regulates VCP ATPase activity and participates in multiple cellular degradation pathways, including endoplasmic reticulum-associated degradation (ERAD) and autophagy 1. It mediates CAV1 transport to lysosomes for degradation and coordinates VCP-dependent clearance of damaged lysosomes 23. In immune cells, UBXN6 serves as an autophagy activator that suppresses inflammatory responses, with upregulation negatively correlating with inflammatory gene profiles in sepsis patients 4. UBXN6 also positively regulates JAK-STAT signaling by stabilizing TYK2 and type I IFNR during viral infection, enhancing interferon-stimulated gene expression 5. In mitophagy, UBXN6 facilitates PRKN recruitment and mitochondrial quality control by promoting mitofusin removal 6. A SNP in UBXN6 (rs1127888) associates with HIV non-progression phenotypes, modulating CAV1 trafficking and viral replication capacity 7. Dysregulation of UBXN6 contributes to pathologies including neurodegenerative diseases and head and neck cancer, where it correlates with endoplasmic reticulum stress responses and tumor immune microenvironment composition 89.