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Therapies targeting the underlying mechanism of <jats:italic>FLNC<\/jats:italic>\u2010related dilated cardiomyopathy remain limited. In this study, we observed that deletion of <jats:italic>Flnc<\/jats:italic> in cardiomyocytes of mice led to prominent ventricular dilation, cardiac dysfunction, and cardiac fibrosis. This phenotype closely resembles <jats:italic>FLNC<\/jats:italic>\u2010related dilated cardiomyopathy in humans. RNA sequencing analysis revealed activation of protein disulfide isomerase (PDI) in <jats:italic>Flnc<\/jats:italic>\u2010deleted cardiac tissues, as confirmed by immunoblotting. Treatment with the specific PDI inhibitor E64FC26 improved cardiac function, reduced cardiac fibrosis, and decreased cardiomyocyte apoptosis in cardiomyocyte\u2010specific <jats:italic>Flnc<\/jats:italic>\u2010deleted mice. We provide evidence that PDI is involved in the cardiac remodeling induced by Filamin C deficiency, and that treatment with the PDI inhibitor resulted in beneficial effects in mice with dilated cardiomyopathy caused by <jats:italic>Flnc<\/jats:italic> deletion. Our findings suggest that PDI could be a promising therapeutic target for <jats:italic>FLNC<\/jats:italic>\u2010related dilated cardiomyopathy.<\/jats:p>","DOI":"10.1111\/jcmm.70493","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T13:21:28Z","timestamp":1742304088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Protein Disulfide Isomerase Involvement in Dilated Cardiomyopathy Caused by Filamin C Deficiency in Male Mice"],"prefix":"10.1111","volume":"29","author":[{"given":"He","family":"Xuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghao","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anteng","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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