UFD1 is a core component of the p97–UFD1–NPLOC4 AAA-ATPase complex that extracts ubiquitinated misfolded proteins from the endoplasmic reticulum and delivers them to the proteasome for degradation. This ternary complex recognizes polyubiquitinated substrates and translocates them from the ER membrane to the cytoplasm, a process essential for protein quality control. Beyond ER-associated degradation, UFD1 participates in multiple cellular pathways: the complex regulates spindle disassembly during mitosis and nuclear envelope reformation, and it negatively suppresses type I interferon production by recruiting ubiquitin ligase RNF125 to degrade the viral sensor RIG-I. Recent studies implicate UFD1 in autophagy initiation and aggresome clearance via selective autophagy, with the p97–UFD1–NPLOC4 complex working alongside chaperones and autophagy receptors to disassemble and remove protein aggregates 1. Haploinsufficiency of UFD1L contributes to 22q11.2 deletion syndrome, characterized by congenital cardiac and craniofacial defects 2, reflecting the gene's critical role in ectoderm-derived tissue development. The p97–UFD1–NPLOC4 axis represents a therapeutic target in cancer and immunotherapy resistance; inhibitors disrupting this complex show promise for blocking unwanted protein degradation, and enhancing FTO degradation via this pathway can restore antitumor immunity 3.