2. Academic Validation
  3. Lysosomal homeostasis regulates myocardial ischemia-reperfusion injury through autophagy pathway

Lysosomal homeostasis regulates myocardial ischemia-reperfusion injury through autophagy pathway

  • Sci Rep. 2025 Oct 22;15(1):36952. doi: 10.1038/s41598-025-20853-6.
Yi Li # 1 2 3,  Yanfang Liu # 4 2 3,  Hui Wu 5 6 7,  Songlin Zhang 8 9 10,  Di Liu 11,  Xiaoli Huang 12,  Gang Zhou 4 2 3,  Dong Zhang 4 2 3,  Xiaoting Yang 4 2 3,  Tian Zhou 4 2 3,  Yan Xiong 4 2 3
Affiliations

Affiliations

  • 1 Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, China.
  • 2 Hubei Key Laboratory of Ischemic Cardiovascular Disease, Yichang, China.
  • 3 Hubei Provincial Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China.
  • 4 Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, China.
  • 5 Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, China. wuhui@ctgu.edu.cn.
  • 6 Hubei Key Laboratory of Ischemic Cardiovascular Disease, Yichang, China. wuhui@ctgu.edu.cn.
  • 7 Hubei Provincial Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China. wuhui@ctgu.edu.cn.
  • 8 Department of Cardiothoracic Surgery, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, China. anyecho11try@163.com.
  • 9 Hubei Key Laboratory of Ischemic Cardiovascular Disease, Yichang, China. anyecho11try@163.com.
  • 10 Hubei Provincial Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China. anyecho11try@163.com.
  • 11 Department of Cardiology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huang Shi, China.
  • 12 Department of Respiratory and Critical Care Medicine, Yiling People's Hospital of Yichang, Yichang, China.
  • # Contributed equally.
PMID: 41125732 DOI: 10.1038/s41598-025-20853-6
Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-025-20853-6.

Keywords

Autophagy; Autosis; Ischemia-reperfusion injury; Lysosome homeostasis.

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