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Autocrine Motility Factor Receptor (AMFR) is a recently identified ER\u2010phagy regulator, whose function under myocardial pathology remains poorly understood. Here, it is found that FAM134B\u2010mediated ER\u2010phagy activity is elevated in fibrotic mouse heart tissues post\u2010MI and in cardiac fibroblasts stimulated by TGF\u2010\u03b21. AMFR knockout in mice aggravated cardiac fibrosis post\u2010MI and worsened cardiac function, with scRNA\u2010seq analysis demonstrating that AMFR\u2010null cardiac fibroblasts exhibit a myofibroblast phenotype. Simultaneously, AMFR overexpression in cardiac fibroblasts reduces the expression of profibrogenic proteins in response to TGF\u2010\u03b21 stimulation. AMFR regulates ER\u2010phagy flux and turnover of FAM134B, which leads to the suppression of cardiac fibroblasts activation. Mechanistically, AMFR catalyzed K27\u2010linked (predominant) and K33\u2010linked ubiquitination of FAM134B and enhanced ER\u2010phagy flux, thereby inhibiting the phosphorylation of mTORC1 downstream targets such as S6K1 and 4E\u2010BP. These findings highlight the therapeutic potential of AMFR\u2010driven ER\u2010phagy in suppressing cardiac fibrosis post\u2010MI.<\/jats:p>","DOI":"10.1002\/advs.202504552","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T14:25:06Z","timestamp":1752762306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ER\u2010phagy Activation by AMFR Attenuates Cardiac Fibrosis Post\u2010Myocardial Infarction via mTORC1 Pathway"],"prefix":"10.1002","volume":"12","author":[{"given":"Zhixiang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaifan","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"},{"name":"Tongren Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai 200050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boshen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taixi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Jin","sequence":"additional","affiliation":[{"name":"International Medical College of Chongqing Medical University  Chongqing 400010 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7285-413X","authenticated-orcid":false,"given":"Xian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"e_1_2_10_1_1","first-page":"9","volume":"141","author":"Virani S. 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