Deciphering USP8’s pivotal role in cancer: mechanisms, clinical insights and contrasts with its function in pituitary adenomas

The ubiquitin-proteasome system, orchestrated by E1-E2-E3 ubiquitinases, governs protein homeostasis, while deubiquitinating enzymes (DUBs) reverse this process to sustain cellular dynamics. As a key member of the ubiquitin-specific protease (USP) family, USP8 preserves substrate stability via its deubiquitinating activity, and its dysregulation drives the initiation and progression of diverse malignancies—by stabilizing oncogenic substrates to promote tumor proliferation, invasion, and metastasis—while its mutations can contribute to benign pituitary adenomas. This review systematically summarizes USP8’s context-dependent roles in cancer biology, dissects the mechanistic basis for its divergent effects in cancers and pituitary adenoma, and highlights its clinical value as a differential biomarker and unifying therapeutic target across tumor types. Ultimately, this work bridges gaps in cross-tumor USP8 research, provides a theoretical framework for precision tumor diagnosis, and offers novel insights to advance the development of USP-targeted therapies.