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

Zhixiang Wang1, Kaifan Niu1,2, Wei Liu1

  • 1Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 17, 2025
PubMed

Insights

Autocrine Motility Factor Receptor (AMFR) suppresses cardiac fibrosis after myocardial infarction by enhancing ER-phagy. AMFR regulates FAM134B turnover, reducing fibroblast activation and improving heart function.

Area of Science:

  • Cardiovascular Biology
  • Cellular Autophagy
  • Molecular Mechanisms of Fibrosis

Background:

  • Progressive cardiac fibrosis post myocardial infarction (MI) contributes to pathological remodeling and heart failure.
  • The role of endoplasmic reticulum-selective autophagy (ER-phagy) in cardiac fibrosis is not well understood.
  • Autocrine Motility Factor Receptor (AMFR), an ER-phagy regulator, has an unclear function in myocardial pathology.

Purpose of the Study:

  • To investigate the role of AMFR in cardiac fibrosis following myocardial infarction.
  • To elucidate the mechanism by which AMFR influences ER-phagy and cardiac fibroblast activation.
  • To assess the therapeutic potential of AMFR-mediated ER-phagy in mitigating cardiac fibrosis.

Main Methods:

  • Analysis of ER-phagy activity in fibrotic mouse heart tissues and TGF-β1-stimulated cardiac fibroblasts.
  • Assessment of cardiac function and fibrosis in AMFR knockout mice post-MI.
  • Single-cell RNA sequencing (scRNA-seq) of cardiac fibroblasts.
  • Investigation of AMFR's effect on profibrogenic protein expression and ER-phagy flux.
  • Ubiquitination assays and analysis of mTORC1 signaling pathway components.

Main Results:

  • FAM134B-mediated ER-phagy activity was elevated in fibrotic hearts post-MI and in response to TGF-β1.
  • AMFR knockout exacerbated cardiac fibrosis and worsened cardiac function post-MI.
  • AMFR-null cardiac fibroblasts displayed a myofibroblast phenotype, while AMFR overexpression suppressed profibrogenic markers.
  • AMFR was found to regulate ER-phagy flux and FAM134B turnover, inhibiting cardiac fibroblast activation.
  • AMFR catalyzed ubiquitination of FAM134B, enhancing ER-phagy and suppressing mTORC1 signaling.

Conclusions:

  • AMFR plays a protective role against cardiac fibrosis post-MI by enhancing ER-phagy.
  • AMFR-mediated ER-phagy suppresses cardiac fibroblast activation and myofibroblast differentiation.
  • AMFR's regulation of FAM134B ubiquitination and ER-phagy flux offers a potential therapeutic target for heart failure treatment.
Keywords:
AMFRER‐phagyFAM134Bfibroblast activationmTORC1myocardial infarction

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