Spermidine alleviates sepsis-induced cardiomyopathy by improving mitochondrial quality and quantity via a Metallothionein 1-dependent antioxidant pathway

  • Phytomedicine. 2026 Jun:155:158174. doi: 10.1016/j.phymed.2026.158174.
Shiyun Long  1 ,  Jiaxin Sun  2 ,  Yaguang Wu  3 ,  Jia Yi  1 ,  Shuang Ren  1 ,  Xiaoping Ran  1 ,  Xiaofeng Li  1 ,  Gautam Sethi  4 ,  Zhenchun Luo  5 ,  Chenyang Duan  6
Affiliations
  • 1. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
  • 2. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Anesthesiology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, PR China.
  • 3. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Dermatology, Southwest Hospital, Army Medical University, Chongqing, PR China.
  • 4. Department of Pharmacology, National University of Singapore, Singapore, 117600, Singapore. Electronic address: [email protected].
  • 5. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Department of Intensive Care Unit, Chongqing City Hospital of Traditional Chinese Medicine, Chongqing, PR China. Electronic address: [email protected].
  • 6. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China. Electronic address: [email protected].
PMID: 42013738 DOI: 10.1016/j.phymed.2026.158174
Abstract

Background: Sepsis-induced cardiomyopathy (SICM) is characterized by mitochondrial dysfunction, impaired mitophagic flux, and overwhelming oxidative stress. Spermidine (SPD), a natural polyamine known to enhance Autophagy and preserve cardiac function in aging and metabolic disorders, has not been systematically evaluated in the context of septic cardiomyopathy.

Purpose: To determine the therapeutic potential and mechanistic basis of SPD in septic cardiac dysfunction.

Methods: Network pharmacology, RNA Sequencing, a cecal ligation and puncture (CLP) mouse model, and multiple cellular assays were integrated to assess the protective actions of SPD. Mitochondrial function, Mitophagy flux, and oxidative stress were evaluated using transmission electron microscopy (TEM), immunohistochemistry (IHC), Western blotting, structured illumination microscopy (SIM), mitochondrial membrane potential assays, oxygen consumption rate (OCR) analysis, and mitochondrial DNA (mtDNA) quantification. Transcriptomic clustering and pathway enrichment identified molecular targets, which were validated through siRNA-mediated gene silencing.

Results: SPD markedly attenuated SICM in vivo and in vitro by improving both mitochondrial quantity and quality. It restored sepsis-impaired Mitophagy by upregulating LC3B and Atg7, promoting autophagosome maturation, and enhancing cellular ubiquitination. Transcriptomic profiling highlighted metallothionein-1 (MT1) as a key node in metal-ion response pathways. SPD activated the NRF2-MT1-SOD2 antioxidant axis, reduced mitochondrial Reactive Oxygen Species (mtROS) under lipopolysaccharide (LPS) stimulation, and reversed sepsis-induced suppression of SOD2. MT1 knockdown abolished SPD-mediated SOD2 stabilization and mtROS clearance, confirming its essential role in SPD's cardioprotective effects.

Conclusion: SPD mitigates SICM by orchestrating the restoration of mitochondrial quality control, normalization of mitophagic flux, and stabilization of cellular redox homeostasis. These findings support SPD as a promising therapeutic candidate for septic cardiomyopathy.

Keywords
Autophagy; MT1; Mitochondria; ROS; Sepsis; Spermidine.
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