CTSH (cathepsin H) is a lysosomal cysteine protease with critical roles in protein degradation and cellular homeostasis. The enzyme functions as both an aminopeptidase and endopeptidase, contributing to lysosomal protein catabolism and various cellular processes 1. CTSH exhibits significant disease relevance across multiple conditions. In Alzheimer's disease, CTSH represents a genetic risk factor where increased expression correlates with disease susceptibility 23. The protective variant rs2289702 reduces CTSH expression and enhances microglial phagocytosis of amyloid-β peptides 2. Mechanistically, CTSH is regulated by DNA methylation, with proinflammatory cytokines inducing hypermethylation in intron 1, leading to transcriptional downregulation 1. In type 1 diabetes, genetic variants affect methylation variability, influencing environmental sensitivity and beta-cell function 1. CTSH also plays roles in cancer biology, where it correlates with chemoresistance in bladder cancer through semi-squamatization mechanisms 4, and genetic variants influence lung cancer risk in surfactant-related pathways 5. Clinical significance extends to its involvement in microglial phagocytosis regulation and potential as a therapeutic target across neurodegenerative and oncological conditions.