USP11 is an X-linked deubiquitinase that removes ubiquitin from target proteins to regulate their stability and function across multiple cellular contexts. As a cysteine-type deubiquitinase localized to the cytosol and nucleus, USP11 modulates diverse substrates including transcription factors, metabolic enzymes, and signaling proteins. In normal physiology, USP11 regulates spermatogonial stem cell proliferation via the HOXC5/WNT/β-catenin pathway 1 and protects against intervertebral disc degeneration by stabilizing Sirt3 and limiting ferroptosis 2. However, USP11 promotes aggressive cancer phenotypes. In prostate cancer, it increases androgen receptor and c-Myc stability and transcription 3, while in breast cancer it stabilizes PGAM5 to activate ferroptosis-related proteins 4. USP11 also facilitates bladder cancer chemoresistance via MYC deubiquitination 5 and promotes neuroblastoma progression by sustaining transcription elongation through TCEAL1 6. In endothelial cells, USP11 enhances VEGFR2-driven angiogenesis via the PRDX2/c-MYC axis 7. Recent evidence suggests USP11 escapes X-inactivation in females, leading to higher expression and increased vulnerability to tau pathology and Alzheimer's disease in women 8. Notably, USP11 antagonizes PTEN tumor suppression in cancer-specific contexts. These findings identify USP11 as a potential therapeutic target, with USP11 inhibitors such as mitoxantrone showing promise in preclinical models of radiation-induced pneumonitis 9.