CTSO (cathepsin O) is a cysteine-type endopeptidase located on chromosome 4-q32 that functions in cellular protein degradation and turnover 1. The gene contains eight coding exons spanning over 30 kb, with a unique chr4 organization distinct from other cysteine proteinases 1. CTSO is a papain-family cysteine protease expressed in vascular tissues and immune cells 2. It regulates vascular smooth muscle cell (VSMC) migration and adhesion through direct interaction with fibronectin, controlling extracellular matrix deposition and VSMC stiffness 2. In cancer biology, CTSO functions as a protease that reduces BRCA1 and ZNF423 protein levels through cysteine proteinase-mediated degradation, modulating tamoxifen sensitivity in estrogen receptor α-positive breast cancer 3. SNP variants near CTSO affect CTSO expression levels and confer differential drug resistance profiles to tamoxifen and PARP inhibitors 3. Disease relevance includes rare CTSO missense variants causing reduced secretion in familial intracranial aneurysm through impaired VSMC function and excessive fibronectin accumulation 2. CTSO also serves as a biomarker in sepsis-associated acute respiratory distress syndrome, with expression in immune cells correlating with patient outcomes 4. Mendelian randomization analysis identified CTSO as a risk factor for non-endometrioid endometrial cancer 5. These findings establish CTSO as a multifunctional proteolytic enzyme with roles in vascular remodeling, cancer chemotherapy resistance, and immune-mediated inflammatory diseases.