2. Academic Validation
  3. Neutrophil Irgm1 ameliorates sepsis-induced myocardial dysfunction by promoting Alox15 degradation

Neutrophil Irgm1 ameliorates sepsis-induced myocardial dysfunction by promoting Alox15 degradation

  • Redox Biol. 2026 May:92:104104. doi: 10.1016/j.redox.2026.104104.
Zeng Wang 1,  Jiaxiang Sun 2,  Mingyang Wang 1,  Lai Wei 1,  Fengyi Liu 3,  Wenhua Liu 4,  Yige Liu 1,  Jiaxin Wang 1,  Fujian Tan 1,  Bo Yu 5,  Zhiqiang Li 6,  Shaohong Fang 7,  Yong Sun 8
Affiliations

Affiliations

  • 1 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China.
  • 2 The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China; Department of Cardiothoracic Surgery, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, 150023, China.
  • 3 The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China; Department of Integrated Chinese and Western Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 4 Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 5 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University, Harbin, Heilongjiang, 150081, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China. Electronic address: [email protected].
  • 6 Department of Cardiothoracic Surgery, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, 150023, China. Electronic address: [email protected].
  • 7 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University, Harbin, Heilongjiang, 150081, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China. Electronic address: [email protected].
  • 8 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Nangang District, Harbin, 150081, China. Electronic address: [email protected].
PMID: 41795420 DOI: 10.1016/j.redox.2026.104104
Abstract

Sepsis-induced myocardial dysfunction (SIMD), a severe sepsis complication, is characterized by immune dysregulation, with neutrophils playing a central role. While the immunity-related GTPase family M protein (IRGM) in humans and its murine ortholog Irgm1 are key immune regulators, the precise contribution of neutrophil Irgm1 to SIMD pathogenesis remains unclear. This study aims to explore the involvement of neutrophil Irgm1 in SIMD and uncover its mechanisms. This research found that IRGM expression was upregulated in peripheral blood neutrophils from patients with SIMD and inversely correlated with disease severity. In mice, neutrophil-specific Irgm1 deficiency worsened CLP-induced cardiac dysfunction and myocardial inflammation. Mechanistically, Irgm1 interacted with the E3 ubiquitin Ligase RING finger protein 213 (RNF213) to facilitate 15-lipoxygenase (Alox15) ubiquitination and degradation, thereby inhibiting neutrophil Ferroptosis and suppressing the production of 15-HETE, which alleviates SIMD. In patients with SIMD, the expression levels of Alox15 and the concentrations of 15-HETE were positively correlated with disease severity. Notably, intraperitoneal administration of Alox15-targeting drug PD146176 significantly improved cardiac function in SIMD mice. Collectively, this study highlights the pivotal role of the Irgm1 in attenuating SIMD by restraining neutrophil Ferroptosis and 15-HETE production. Irgm1 may serve as a promising prognostic biomarker and a valuable therapeutic target for SIMD.

Keywords

Alox15; Ferroptosis; IRGM/Irgm1; Neutrophil; Sepsis-induced myocardial dysfunction; Ubiquitination.

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