2. Academic Validation
  3. ACOD1-itaconate in macrophage attenuates oxidative stress and inflammation in benign airway stenosis by upregulating and transferring FTH1

ACOD1-itaconate in macrophage attenuates oxidative stress and inflammation in benign airway stenosis by upregulating and transferring FTH1

  • Redox Biol. 2026 May:92:104133. doi: 10.1016/j.redox.2026.104133.
YiLin Chen 1,  ChengFei Xu 2,  Tao Luo 1,  DongChen Shi 1,  XinYi Guo 3,  ChengCheng Yang 1,  YuChao Dong 1,  HaiDong Huang 1,  YiFei Zhang 1,  Zhe Zong 4,  XiaoMin Wang 4,  ZhiRu Xu 5,  Yue Shi 5,  ChaoFeng Han 6,  Hui Shi 7,  Chong Bai 8
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
  • 2 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China; Department of Critical Care Medicine, Jinling Hospital Affiliated Hospital of Nanjing University, Nanjing, China.
  • 3 Department of Information, No. 990 Hospital of the Chinese People's Liberation Army Joint Logistic Support Force, ZhuMaDian, China.
  • 4 Department of Critical Care Medicine, Jinling Hospital Affiliated Hospital of Nanjing University, Nanjing, China.
  • 5 National Key Laboratory of Lead Druggability Research, China State Institute of Pharmaceutical Industry, Shanghai, China.
  • 6 Department of Histology and Embryology, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China. Electronic address: [email protected].
  • 7 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: [email protected].
  • 8 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: [email protected].
PMID: 41865719 DOI: 10.1016/j.redox.2026.104133
Abstract

The oxidative stress of macrophage plays pivotal roles of acute and chronic inflammation and chronic fibrotic phases, in which the metabolic mechanism needs to be further explored. In our research, multi-omics analyses of human and murine during Benign airway stenosis (BAS) biopsy identified ACOD1 as a hallmark of immunometabolic regulation during acute inflammation stage. ACOD1 knockout aggravated both acute and chronic inflammation, which increased the granulation tissue formation. The ACOD1-itaconate axis, along with its derivative, 4-octyl itaconate (4-OI), orchestrated acute and chronic inflammation, which attenuated the fibrosis of BAS. 4-OI upregulated FTH1 expression in macrophages by activating NRF2, which effectively suppressed oxidative stress and acute inflammation. Furthermore, 4-OI promoted the packaging of FTH1 into macrophage-derived exosomes, which were transferred to fibroblasts in a SCARA5-dependent manner, inducing fibroblast Ferroptosis and alleviating chronic fibrosis. In sum, this study illustrates that the ACOD1-itaconate metabolic axis decreases oxidative stress and inflammation in macrophage, which attenuates fibrosis by inducing FTH1 transfer, offering a therapeutic target for fibrotic airway diseases.

Keywords

Benign airway stenosis; Fibrosis; Inflammation; Itaconate; Macrophage.

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