USP26 is a deubiquitinase that regulates protein stability through lysine-48-linked deubiquitination 1. In testicular tissue, USP26 localizes primarily to Leydig cell nuclei and colocalizes with androgen receptor, regulating androgen receptor signaling and early spermatogenesis 2. USP26 also stabilizes polycomb repressive complex 1 components (CBX4/CBX6) during somatic cell reprogramming 3. Beyond reproductive function, USP26 has emerged as an oncogenic deubiquitinase in multiple cancer types. In hepatocellular carcinoma, HBV-induced USP26 stabilizes SIRT1 through deubiquitination, promoting proliferation and impairing apoptosis 4. In colorectal cancer, USP26 deubiquitinates PRKN at K129, restraining mitophagy activation and driving tumorigenesis 5. In breast cancer, acetylation-dependent USP26 stabilizes BAG3 co-chaperone, enhancing cell proliferation and metastasis 6. In cervical cancer, USP26 stabilizes the tumor suppressor KLF6, paradoxically inhibiting proliferation and migration 7. Regarding infertility associations, meta-analyses show no significant overall association between common USP26 mutations and male infertility, though specific variants (c.1737G>A, cluster mutations) may have modest roles 89. USP26 represents a clinically relevant therapeutic target across multiple cancer types.