YOD1 is a deubiquitinating enzyme that removes conjugated ubiquitin from protein substrates, primarily functioning in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins and in macroautophagy. It catalyzes deubiquitination of K27-, K29-, K33-, and K11-linked polyubiquitin chains, facilitating substrate threading through the VCP/p97 pore by trimming ubiquitin chains that would otherwise obstruct passage. YOD1 also participates in lysosomal homeostasis by recruiting VCP and other factors to damaged lysosomes to remove K48-linked ubiquitin chains and facilitate autophagosome formation. YOD1 has emerged as a critical regulator in multiple disease contexts. In triple-negative breast cancer, YOD1 stabilizes CDK1 through deubiquitination, promoting cell proliferation and drug resistance 1. In cardiac hypertrophy, YOD1 removes K48-linked ubiquitin chains from STAT3 at its K97 site, stabilizing STAT3 and driving pathological remodeling 2. YOD1 also protects against MRSA sepsis-induced disseminated intravascular coagulation by deubiquitinating NLRP3 inflammasome components 3, sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2 4, and regulates oxidative stress in Parkinson's disease through PKM2 deubiquitination 5. In clear cell renal carcinoma, YOD1 suppresses metastasis by stabilizing the transcriptional repressor ZNF24 6. Genetic and pharmacological approaches targeting YOD1 show therapeutic potential across these disease contexts, positioning YOD1 as a viable drug target 7.