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While\n                    <jats:italic>TMEM43<\/jats:italic>\n                    has been identified as an ARVC\u2010associated gene, molecular links between\n                    <jats:italic>TMEM43<\/jats:italic>\n                    mutations and electrophysiological abnormalities in ARVC remain largely elusive. Here, using induced\u2010pluripotent\u2010stem\u2010cell\u2010derived cardiomyocytes (iPSC\u2010CMs) and knock\u2010in mice as models, it is demonstrated that a novel\n                    <jats:italic>TMEM43<\/jats:italic>\n                    mutation (TMEM43\u2010P386S) causes Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dysregulation that leads to arrhythmic phenotypes in ARVC, which can be prevented by flecainide. Mechanistically,\n                    <jats:italic>TMEM43<\/jats:italic>\n                    interacts with lamin B2, and the TMEM43\u2010P386S mutation induces lamin B2 mislocalization and abnormal nuclear envelope structure in ARVC iPSC\u2010CMs, resulting in decreased chromatin opening of promoters associated with downregulated genes, including ryanodine receptor 2 (\n                    <jats:italic>RYR2<\/jats:italic>\n                    ).\n                    <jats:italic>RYR2<\/jats:italic>\n                    s are downregulated and grouped into smaller clusters in ARVC iPSC\u2010CMs, as revealed by Tau\u2010STED super\u2010resolution imaging, contributing to enhanced\n                    <jats:italic>RYR2<\/jats:italic>\n                    \u2010mediated sarcoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak. These findings represent a novel mechanism underlying arrhythmogenesis in\n                    <jats:italic>TMEM43<\/jats:italic>\n                    \u2010related ARVC and point to\n                    <jats:italic>RYR2<\/jats:italic>\n                    stabilization as a potential therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512058","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T10:34:59Z","timestamp":1757932499000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decreased\n                    <i>RYR2<\/i>\n                    Cluster Size and Abnormal SR Ca\n                    <sup>2+<\/sup>\n                    Release Contribute to Arrhythmogenesis in\n                    <i>TMEM43<\/i>\n                    \u2010Related ARVC"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiaxi","family":"Shen","sequence":"first","affiliation":[{"name":"Key Laboratory of Combined Multi\u2010Organ Transplantation Ministry of Public Health The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310003 China"},{"name":"Institute of Translational Medicine Zhejiang University  Hangzhou 310029 China"},{"name":"Key Laboratory of Precision Prevention and Treatment for Atherosclerotic Diseases of Zhejiang Province Department of Cardiology The First Affiliated Hospital of Ningbo University  Ningbo 315010 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaochen","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combined Multi\u2010Organ Transplantation Ministry of Public Health The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310003 China"},{"name":"Institute of Translational Medicine Zhejiang University  Hangzhou 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