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The PLN R9C mutation causes early\u2010onset dilated cardiomyopathy (DCM) and premature death, yet the mechanisms underlying its pathogenic remodeling remain unclear. In this study, patient\u2010specific induced pluripotent stem cell\u2010derived cardiomyocytes (iPSC\u2010CMs) harboring the PLN R9C and their isogenic corrected controls are generated to investigate the molecular and functional consequences of the mutation. At baseline, PLN R9C iPSC\u2010CMs exhibit near\u2010normal calcium handling but blunt\u00a0\u03b2\u2010adrenergic signaling and slightly enhanced contractility. Under functional stress induced by a pro\u2010maturation medium, mutant cells develop marked sarcomere disarray, impaired calcium handling, elevated diastolic calcium, and reduced contractile force, whereas corrected cells show adaptive improvement. Transcriptomic and biochemical analyses reveal activation of proteostasis pathways but accumulation of PLN pentamers and impaired autophagic flux, suggesting that autophagic overload contributes to functional remodeling. Treatment with the autophagy activator metformin mitigates sarcomere disorganization, restores calcium homeostasis, and improves contractility in patient\u2010derived iPSC\u2010CMs. These findings are further validated in wild\u2010type and genome\u2010engineered PLN R9C iPSC\u2010CMs. Collectively, the study demonstrates that PLN R9C drives stress\u2010induced pathological remodeling by disrupting proteostasis, and that enhancing autophagic flux offers a promising therapeutic strategy for DCM patients carrying PLN mutations.<\/jats:p>","DOI":"10.1002\/advs.202511480","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T03:57:24Z","timestamp":1764302244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Promoting Autophagy Mitigates Stress\u2010Induced Remodeling in Patient iPSC\u2010CMs with the Phospholamban R9C Mutation"],"prefix":"10.1002","volume":"13","author":[{"given":"Qi","family":"Yu","sequence":"first","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh PA 15261 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawei","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Clemson University  Clemson SC 29634 USA"},{"name":"Center for Human Genetics Clemson University  Greenwood SC 29646 USA"},{"name":"College of Fisheries Henan Normal University  Xinxiang Henan 453007 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Barndt","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh PA 15261 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