The enzyme is essential for cell-cycle progression, DNA-damage repair, and transforming growth factor-beta (TGF-β)/SMA/mothers against decapentaplegic homolog (Smad), Wnt/β-catenin, and Notch signaling by stabilizing key proteins such as myeloid cell leukemia-1 (MCL-1), axis inhibition protein (AXIN), SMAD4, and Itchy E3 ubiquitin protein ligase (ITCH), thereby controlling apoptosis, stem-cell maintenance, and epithelial–mesenchymal transition; loss-of-function or mutations in USP9X lead to developmental defects and increased susceptibility to various cancers [46]. The gene discussed is ITCH; the disease is cancer.