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<p>This study aims to elucidate the dual role of lysosomal homeostasis in regulating autophagic flux during myocardial ischemia/reperfusion injury (MIRI). Using a rat MIRI model and primary myocardial cell hypoxia/reoxygenation (HR) model, we assessed the changes in autophagic flux through the intervention of autophagy agonists (TAT-Beclin1), inhibitors (3-MA), lysosomal agonists (Torin1), and inhibitors (Bafilomycin A1) from multiple dimensions. In vitro experiments showed that HR significantly induced the accumulation of autophagosomes, but lysosomal dysfunction resulted in blocked autophagic flux. Intervention with Torin1 increased the autophagolysosome formation rate, while simultaneously reducing cell necrosis (Hoechst/PI staining) and apoptosis (flow cytometry of Annexin V + cells), whereas BafA1 exacerbated the damage. In vivo studies confirmed that after IR, the infarct size increased, and left ventricular ejection fraction (LVEF) decreased. However, 3-MA and Torin1 interventions reduced infarct size and partially restored ejection fraction. Mechanistically, Western blot analysis showed that after HR, SQSTM1/p62 and LC3 accumulated, while LAMP1 degradation occurred. Lysosomal activation alleviated the HR-induced accumulation of autophagic vesicles. This study reveals a vicious cycle of “overactivation of autophagy - lysosomal degradation defects” in MIRI, and targeting lysosomal homeostasis to regulate autophagic flux may serve as a novel therapeutic strategy.</p>

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Lysosomal homeostasis regulates myocardial ischemia-reperfusion injury through autophagy pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • Yi Li,
  • Yanfang Liu,
  • Hui Wu,
  • Songlin Zhang,
  • Di Liu,
  • Xiaoli Huang,
  • Gang Zhou,
  • Dong Zhang,
  • Xiaoting Yang,
  • Tian Zhou,
  • Yan Xiong

摘要

This study aims to elucidate the dual role of lysosomal homeostasis in regulating autophagic flux during myocardial ischemia/reperfusion injury (MIRI). Using a rat MIRI model and primary myocardial cell hypoxia/reoxygenation (HR) model, we assessed the changes in autophagic flux through the intervention of autophagy agonists (TAT-Beclin1), inhibitors (3-MA), lysosomal agonists (Torin1), and inhibitors (Bafilomycin A1) from multiple dimensions. In vitro experiments showed that HR significantly induced the accumulation of autophagosomes, but lysosomal dysfunction resulted in blocked autophagic flux. Intervention with Torin1 increased the autophagolysosome formation rate, while simultaneously reducing cell necrosis (Hoechst/PI staining) and apoptosis (flow cytometry of Annexin V + cells), whereas BafA1 exacerbated the damage. In vivo studies confirmed that after IR, the infarct size increased, and left ventricular ejection fraction (LVEF) decreased. However, 3-MA and Torin1 interventions reduced infarct size and partially restored ejection fraction. Mechanistically, Western blot analysis showed that after HR, SQSTM1/p62 and LC3 accumulated, while LAMP1 degradation occurred. Lysosomal activation alleviated the HR-induced accumulation of autophagic vesicles. This study reveals a vicious cycle of “overactivation of autophagy - lysosomal degradation defects” in MIRI, and targeting lysosomal homeostasis to regulate autophagic flux may serve as a novel therapeutic strategy.