OTUD6A is an X-linked deubiquitinase that catalyzes hydrolysis of K11-, K27-, K29-, K33-, and K48-linked polyubiquitin chains 1. Functionally, OTUD6A stabilizes multiple oncogenic substrates through deubiquitination, including c-Myc in prostate cancer 2, CDC6 in bladder cancer 3, Brg1 and androgen receptor in prostate cancer 4, Drp1 in colorectal cancer 5, and TopBP1 in breast cancer 6. Beyond oncogenic roles, OTUD6A promotes NLRP3 inflammasome activation in macrophages by removing K48-linked chains from NLRP3, exacerbating intestinal inflammation and colitis 1. OTUD6A also suppresses innate immunity by deubiquitinating UBC13, reducing type I interferon production 7. Additionally, OTUD6A antagonizes the tumor-suppressive function of TRIM21 by removing K27-linked ubiquitination from AKT, preserving kinase activity and promoting cancer chemoresistance 8. Clinically, OTUD6A amplification and overexpression correlate with poor prognosis in prostate, bladder, and breast cancers. Its genomic amplification in prostate cancer occurs with mutual exclusivity to FBXW7 and SPOP mutations 4, suggesting OTUD6A represents a distinct oncogenic pathway warranting therapeutic targeting.