2. Academic Validation
  3. IL-35 alleviates ferroptosis in macrophage by activating the NRF2/GPX4 pathway to improve sepsis-induced ARDS

IL-35 alleviates ferroptosis in macrophage by activating the NRF2/GPX4 pathway to improve sepsis-induced ARDS

  • Cytokine. 2025 Dec 9:198:157086. doi: 10.1016/j.cyto.2025.157086.
Panting Liu 1,  Chen Zhang 1,  Minkang Guo 2,  Shanmu Ai 3,  Yisi Zhao 2,  Renjie Luo 2,  Fang Xu 4,  Zhengtao Zhang 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Disease, Chongqing, China.
  • 2 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Emergency, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China.
  • 4 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 5 Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 41370997 DOI: 10.1016/j.cyto.2025.157086
Abstract

Objective: Macrophage M1/M2 polarization is essential to mitigate acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Ferroptosis is pivotal in sepsis-induced ALI and interleukin (IL)-35 has been reported to exert anti-inflammatory effects. Therefore, we aimed to investigate the effect of IL-35 on Ferroptosis and macrophage polarization in ARDS.

Methods: We constructed an in vitro inflammation model using lipopolysaccharide (LPS) to assess the macrophage polarization, Ferroptosis, phagocytosis, and killing effects after IL-35 treatment. A cecal ligation and puncture model was established, and lung injury, Ferroptosis, and macrophage polarization were detected following rIL-35 treatment. The indexes showed changes after the use of an NRF2 inhibitor. Additionally, we quantified the injury and Apoptosis of MLE-12 cells after co-culture with RAW264.7 cells and detected IL-10 expression.

Results: IL-35 blocked LPS-induced polarization of RAW264.7 and bone marrow-derived macrophages to M1 and promoted M2 generation. It up-regulated the NRF2/GPX4 pathway and attenuated Ferroptosis in macrophages. When NRF2 was inhibited, the regulatory effects of IL-35 on the macrophage phenotype and Ferroptosis were reversed. After co-culture with IL-35-treated RAW264.7, the Apoptosis of MLE-12 cells was reduced and IL-10 expression was increased.

Conclusion: IL-35 alleviates ALI by reducing macrophage Ferroptosis and attenuating the activation of proinflammatory macrophages via the NRF2/GPX4 pathway. IL-35-induced macrophages phenotypic remodeling reduce the Apoptosis of lung epithelial cells by secreting IL-10.

Keywords

ALI; Ferroptosis; IL-35; Macrophages; NRF2.

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