Obesity-associated metabolic dysregulation aggravates myocardial ischemia-reperfusion injury through Gls2-mediated ferroptosis

  • Eur J Pharmacol. 2026 Mar 28:1019:178739. doi: 10.1016/j.ejphar.2026.178739.
Taotao Zhou  1 ,  Yang Liu  2 ,  Rong Xiao  3 ,  Baodong Xie  4 ,  Wandong Xie  5 ,  Xionghai Qin  6 ,  Xu Zhan  7 ,  Haobo Sun  8 ,  Donghui Liu  9 ,  Sida Qin  10 ,  Changfu Li  11 ,  Lihua Sun  12 ,  Kai Kang  13
Affiliations
  • 1. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 2. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 3. Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 4. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 5. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 6. Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, China. Electronic address: [email protected].
  • 7. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 8. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 9. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 10. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 11. Research Administration Department, Daqing Longnan Hospital, Daqing, 163311, China. Electronic address: [email protected].
  • 12. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; Department of Pharmacology (Joint International Research Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
  • 13. Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. Electronic address: [email protected].
PMID: 41819522 DOI: 10.1016/j.ejphar.2026.178739
Abstract

Metabolic diseases, including obesity, are becoming increasingly prevalent worldwide. However, the extent to which obesity-associated metabolic dysregulation exacerbates myocardial ischemia-reperfusion (IR) injury, and its specific impact on the patterns of cell death in this context, remain insufficiently understood. In this study, we demonstrate that obesity-associated metabolic dysregulation leads to more severe cardiac IR injury. This effect is not due to increased IR-mediated myocardial Apoptosis, but rather to enhanced IR-induced Ferroptosis. Our findings indicate that obesity-associated metabolic dysregulation aggravates cardiac Ferroptosis primarily by upregulating Glutaminase 2 (Gls2) expression in the heart. Furthermore, inhibition of Gls2 may attenuate IR injury exacerbated by obesity-associated metabolic dysregulation.

Keywords
Ferroptosis; Ischemia-reperfusion; Obesity-associated metabolic dysregulation.
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