TPSD1 (tryptase delta 1) encodes a serine-type endopeptidase that functions as a major neutral protease in mast cells 1. Upon mast cell activation and degranulation, TPSD1-derived tryptase is secreted and contributes to proteolytic processes in tissue microenvironments 1. All circulating human mast cell progenitors have the potential to differentiate into cells expressing TPSD1 alongside other granule proteases including tryptase, chymase, and carboxypeptidase A3 1. TPSD1 expression is clinically relevant in multiple pathological contexts. TPSD1 expression increases in synovial tissue of overweight hip osteoarthritis patients, suggesting a mechanistic link between obesity and joint disease pathology 2. In extrahepatic cholangiocarcinoma, TPSD1+ mast cell populations associate with inflammatory and fibrotic tumor phenotypes linked to worse prognosis 3. TPSD1 variants associate with urticaria susceptibility through effects on mast cell biology and type 2 immune responses 4. In oral squamous cell carcinoma, TPSD1 mutations and altered expression correlate with perineural invasion and poor survival outcomes 5. Additionally, TPSD1 expression differences contribute to transcriptomic heterogeneity in rotator cuff disease 6 and acute myeloid leukemia patient stratification 7. These findings underscore TPSD1's role in immune-inflammatory pathologies and tumor biology.