ER‐phagy Activation by AMFR Attenuates Cardiac Fibrosis Post‐Myocardial Infarction via mTORC1 Pathway

Progressive cardiac fibrosis post myocardial infarction (MI) drives pathological remodeling and heart failure, yet the role of endoplasmic reticulum-selective autophagy (ER-phagy) in this process remains unclear. Autocrine Motility Factor Receptor (AMFR) is a recently identified ER-phagy regulator, whose function under myocardial pathology remains poorly understood. Here, it is found that FAM134B-mediated ER-phagy activity is elevated in fibrotic mouse heart tissues post-MI and in cardiac fibroblasts stimulated by TGF-β1. AMFR knockout in mice aggravated cardiac fibrosis post-MI and worsened cardiac function, with scRNA-seq analysis demonstrating that AMFR-null cardiac fibroblasts exhibit a myofibroblast phenotype. Simultaneously, AMFR overexpression in cardiac fibroblasts reduces the expression of profibrogenic proteins in response to TGF-β1 stimulation. AMFR regulates ER-phagy flux and turnover of FAM134B, which leads to the suppression of cardiac fibroblasts activation. Mechanistically, AMFR catalyzed K27-linked (predominant) and K33-linked ubiquitination of FAM134B and enhanced ER-phagy flux, thereby inhibiting the phosphorylation of mTORC1 downstream targets such as S6K1 and 4E-BP. These findings highlight the therapeutic potential of AMFR-driven ER-phagy in suppressing cardiac fibrosis post-MI.