NPEPPS (puromycin-sensitive aminopeptidase) is a zinc metallopeptidase with broad substrate specificity that plays multiple critical roles in cellular proteolysis and immune function. Primary function involves N-terminal trimming of cytotoxic T-cell epitope precursors and processing of proteasome-derived peptides for MHC class I antigen presentation 1. NPEPPS catalyzes initial peptide processing upstream of ERAP1 and ERAP2 in the antigen-presentation pathway 1. The enzyme digests poly-Q peptides and tau proteins, with differential efficiency between normal and pathological tau variants [UniProt]. Beyond immunology, NPEPPS regulates intracellular cisplatin concentrations by interacting with volume-regulated anion channels (VRACs), controlling drug transport and chemotherapy sensitivity 23. NPEPPS depletion or pharmacologic inhibition sensitizes platinum-resistant bladder cancer cells to cisplatin in vitro, in vivo, and in patient-derived organoids 3. Clinically, NPEPPS is implicated in multiple immune-mediated diseases through genome-wide association studies, including ankylosing spondylitis and psoriasis, with demonstrated genetic interactions with HLA-B27 41. Recent evidence suggests NPEPPS as a potential therapeutic target for coronary atherosclerosis 5 and identifies it as a hub gene in neurodevelopmental disorders 6. The NPEPPS/VRAC expression ratio predicts cisplatin response across multiple cancer cohorts 2, establishing NPEPPS as a druggable biomarker for improving platinum-based chemotherapy outcomes.