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However, its role in arrhythmogenic cardiomyopathy (ACM) remains unknown. Here, we demonstrate that POSTN is significantly elevated in the myocardium of ACM mice and patients. POSTN deficiency alleviates heart dysfunction, reduces cardiac fibrosis and improves survival rates in ACM mice. POSTN is mainly derived from cardiac myofibroblasts and promotes cardiomyocyte necroptosis in vivo and in vitro. Mechanistically, POSTN facilitates cardiomyocyte necroptosis through the integrin\u2010JNK\u2010RIP3\u2010MLKL signaling and induces CCL3 expression via the integrin\u2010JNK\u2010ETS2 pathway. In turn, CCL3 activates cardiac myofibroblasts and stimulates POSTN expression through the NF\u2010\u03baB signaling. Our findings show that POSTN and CCL3 facilitate ACM progression through the POSTN\u2010integrin\u2010JNK\u2010ETS2\u2010CCL3 signaling in cardiomyocytes and CCL3\u2010CCR5\u2010NF\u2010\u03baB\u2010POSTN axis in cardiac myofibroblasts. We further found that pharmacological inhibition of either JNK or CCR5 to target JNK\u2010CCL3\u2010CCR5 axis attenuates subsequent ACM progression in mice by suppressing cardiac fibrosis and cardiomyocyte necroptosis. Therefore, targeting the POSTN\u2010CCL3 feedforward signaling loop may offer a novel therapeutic strategy for patients with ACM.<\/jats:p>","DOI":"10.1002\/advs.77670","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:31:46Z","timestamp":1789101106000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Periostin\u2010CCL3 Feedforward Signaling Loop Promotes Cardiac Fibrosis and Cardiomyocyte Necroptosis in Arrhythmogenic Cardiomyopathy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3846-6052","authenticated-orcid":false,"given":"Tiantian","family":"Wu","sequence":"first","affiliation":[{"name":"Institute For Common Diseases JinJiang Municipal Hospital School of Medicine School of Life Sciences Xiamen University  Xiamen China"},{"name":"State Key Laboratory of Cellular Stress Biology School of Life Sciences State Key Laboratory of Vaccines for Infectious 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