YOD1 is a cysteine-type deubiquitinase that removes conjugated ubiquitin from protein substrates, with critical roles in protein quality control and immune regulation. Mechanistically, YOD1 cleaves K48-, K63-, K11-, K27-, K29-, and K33-linked polyubiquitin chains 1, facilitating endoplasmic reticulum-associated degradation (ERAD) by trimming ubiquitin chains to enable substrate threading through the VCP/p97 pore. Beyond ERAD, YOD1 participates in macroautophagy and lysosomal homeostasis, recruiting VCP and other factors to damaged lysosomes decorated with K48-linked ubiquitin chains to facilitate autophagosome formation 2. YOD1 exhibits multiple disease associations. In cardiac pathology, cardiomyocyte-derived YOD1 promotes pathological hypertrophy by deubiquitinating and stabilizing STAT3 through K48-linked chain removal at lysine 97, enhancing STAT3 nuclear translocation 3. In cancer, YOD1 is upregulated in triple-negative breast cancer (TNBC) tissues and promotes tumorigenesis by stabilizing CDK1 through K48-deubiquitination 4. Conversely, YOD1 provides protective functions in inflammatory conditions: it protects against MRSA sepsis-induced DIC by removing K33-linked ubiquitination of NLRP3 inflammasome 5, and sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2 6. Recent evidence identifies YOD1 as a novel therapeutic target in chr1 kidney disease 7 and diabetic foot ulcers 8, highlighting its broad clinical significance.