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Human-engineered heart tissues consisting of both cardiomyocytes and cardiac fibroblasts faithfully recapitulate key aspects of the human disease, including reduced contractile function, impaired relaxation, and increased prevalence of arrhythmogenic events. While both cardiomyocytes and cardiac fibroblasts show increased intracellular iron levels, cardiomyocytes show higher iron accumulation and reactive oxygen species production. Moreover, iron overload has little effect on the action potential kinetics in engineered heart tissues; however, it impacts the kinetics of the calcium transient, potentially driving arrhythmogenesis. Finally, iron overload decreases force production, in part, through oxidative damage of sarcomeric proteins and iron-based inhibition of myosin. Our results reveal insights into the cellular and molecular mechanisms of human IOC pathogenesis and establish in vitro models that can be harnessed for mechanistic and translational studies.<\/jats:p>","DOI":"10.1091\/mbc.e26-02-0063","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:51:21Z","timestamp":1778691081000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular and cellular determinants of human iron overload cardiomyopathy"],"prefix":"10.1091","volume":"37","author":[{"given":"Sayli S.","family":"Modak","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110"},{"name":"Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, 63130"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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