MDH1 K298 succinylation stabilizes redox homeostasis to protect against cardiac ferroptosis in ischemia-reperfusion injury

  • J Adv Res. 2026 Jul 6:S2090-1232(26)00529-1. doi: 10.1016/j.jare.2026.07.011.
Haodong Li  1 ,  Jie Liu  2 ,  Junting Ren  2 ,  Manyu Gong  3 ,  Yanwei Zhang  2 ,  Mengxing Cheng  2 ,  Yapeng Li  4 ,  Hao Wang  2 ,  Siyu Wang  2 ,  Xintong Li  5 ,  Shihua Lv  6 ,  Ying Zhang  2 ,  Shasha Fan  2 ,  Xiaoning Chen  4 ,  Mingyu Yang  2 ,  Wei Liu  2 ,  Xiaoping Leng  7 ,  Mengmeng Li  8 ,  Yong Zhang  9 ,  Ying Zhang  10
Affiliations
  • 1. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin 150081, China; Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 2. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin 150081, China.
  • 3. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine, Tianjin 300193, China.
  • 4. The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
  • 5. Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  • 6. Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • 7. Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: [email protected].
  • 8. Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China. Electronic address: [email protected].
  • 9. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin 150081, China. Electronic address: [email protected].
  • 10. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin 150081, China; Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Department of Pharmacology, College of Pharmacy, and Department of Ultrasound, the Second Affiliated Hospital, Harbin Medical University, 157 Baojian Road, Harbin 150081, China. Electronic address: [email protected].
PMID: 42409167 DOI: 10.1016/j.jare.2026.07.011
Abstract

Introduction: Lysine succinylation is an emerging post-translational modification critically involved in cardiovascular pathophysiology. Malate dehydrogenase 1 (MDH1), a core enzyme of the malate-aspartate shuttle that maintains cardiomyocyte redox homeostasis, is implicated in myocardial injury, yet the regulatory role and specific mechanism of MDH1 succinylation in myocardial ischemia/reperfusion (I/R) injury remain incompletely understood.

Objective: This study aims to elucidate the functional role and underlying molecular mechanism of site-specific lysine succinylation of MDH1 in myocardial I/R injury.

Methods: Global succinylome profiling was performed on cardiac tissue from murine I/R models. Target succinylation was validated by immunoprecipitation and Western blot. AAV9 vectors encoding wild-type MDH1 (MDH1-WT) or succinylation-deficient mutant (MDH1-K298R) were constructed for cardiac-specific delivery. Molecular docking and co-immunoprecipitation identified the upstream succinyltransferase, and virtual screening identified Ethyl rosmarinate (ER) as a Carnitine palmitoyltransferase 1A (CPT1A)-stabilizing compound.

Results: MDH1 K298 succinylation was significantly decreased in I/R-injured hearts compared with sham-operated control hearts. In vivo cardiac overexpression of MDH1-WT suppressed Ferroptosis and ameliorated myocardial I/R injury, whereas MDH1-K298R failed to confer such protection, indicating that the cardioprotective effect of MDH1 is dependent on K298 succinylation. Mechanistically, K298 succinylation enhanced MDH1 protein stability by inhibiting its ubiquitin-proteasomal degradation, thereby preserving redox homeostasis required for Glutathione Peroxidase 4 (GPX4) activity. Importantly, CPT1A was identified as the succinyltransferase responsible for MDH1 K298 succinylation. ER alleviated myocardial I/R injury by preventing Carnitine palmitoyltransferase 1A (CPT1A) degradation and consequently enhancing MDH1 K298 succinylation.

Conclusion: Our findings uncover a critical cardioprotective role of the CPT1A-MDH1 succinylation axis via suppressing Ferroptosis during myocardial I/R injury, and identify ER as a CPT1A-stabilizing compound with promising therapeutic potential for ischemic heart disease.

Keywords
CPT1A; Ethyl rosmarinate; Ferroptosis; MDH1; Myocardial ischemia–reperfusion injury; Succinylation.
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