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BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type\u2013specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In\n                    <jats:italic>\n                      BAG3\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    CFs, we observed an increased sensitivity to TGF-\u03b2 signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-\u03b2 receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic\n                    <jats:italic>BAG3<\/jats:italic>\n                    variants.\n                    <jats:italic>BAG3<\/jats:italic>\n                    pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type\u2013specific aspects of cardiac disease.\n                  <\/jats:p>","DOI":"10.1172\/jci181630","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T14:00:42Z","timestamp":1735740042000},"source":"Crossref","is-referenced-by-count":23,"title":["Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy"],"prefix":"10.1172","volume":"135","author":[{"given":"Bryan Z.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaretha A.J.","family":"Morsink","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New 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