TMPRSS6 encodes matriptase-2, a membrane-bound serine protease highly expressed in the liver that plays a critical role in iron homeostasis 1. The primary function of TMPRSS6 is to negatively regulate hepcidin expression, the master systemic iron-regulatory hormone 21. TMPRSS6 accomplishes this through proteolytic cleavage of hemojuvelin (HJV), a cell surface regulator of hepcidin expression, thereby promoting iron absorption 2. Loss-of-function mutations in TMPRSS6 impair this negative regulation, causing excessive hepcidin production that restricts iron absorption and leads to iron-refractory iron deficiency anemia (IRIDA), a rare hereditary microcytic anemia characterized by resistance to oral iron supplementation 13. IRIDA patients typically require intravenous iron therapy, though responses vary 3. Beyond iron metabolism, TMPRSS6 variants have been associated with myocardial and multi-organ interstitial fibrosis in large population studies, suggesting broader physiological roles 45. Understanding TMPRSS6 biology has enabled development of targeted therapeutic approaches for iron homeostasis disorders 1. Notably, a recent meta-analysis found no significant association between the common TMPRSS6 rs855791 polymorphism and anemia risk, highlighting the complexity of genetic contributions to iron deficiency 6.