2. Academic Validation
  3. 4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING

4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING

  • Cell Rep. 2023 Feb 28;42(3):112145. doi: 10.1016/j.celrep.2023.112145.
Weizhen Li 1,  Yangguang Li 2,  Jiaqi Kang 2,  Haiyang Jiang 3,  Wenbin Gong 4,  Lijuan Chen 3,  Cunxia Wu 2,  Mingda Liu 5,  Xiuwen Wu 6,  Yun Zhao 7,  Jianan Ren 8
Affiliations

Affiliations

  • 1 School of Medicine, Anhui University of Science and Technology, Huainan 232000, China; Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, China; Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 2 Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, China.
  • 3 Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 4 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
  • 5 The Core Laboratory, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 6 Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, China. Electronic address: [email protected].
  • 7 Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China. Electronic address: [email protected].
  • 8 School of Medicine, Anhui University of Science and Technology, Huainan 232000, China; Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, China. Electronic address: [email protected].
PMID: 36862550 DOI: 10.1016/j.celrep.2023.112145
Abstract

The Krebs cycle-derived metabolite itaconate, whose production is catalyzed by immune response gene 1 (IRG1), has potential to link immunity and metabolism in activated macrophages through alkylation or competitive inhibition of target proteins. In support of this, our previous study demonstrated that the stimulator of interferon genes (STING) signaling platform functions as a hub in macrophage immunity and has a profound impact on the prognosis of sepsis. Interestingly, we find that itaconate, an endogenous immunomodulator, can significantly inhibit the activation of STING signaling. Moreover, 4-octyl itaconate (4-OI), which is a permeable itaconate derivative, can alkylate cysteine sites 65, 71, 88, and 147 of STING, thereby inhibiting its phosphorylation. Furthermore, itaconate and 4-OI inhibit the production of inflammatory factors in sepsis models. Our results broaden the knowledge on the role of the IRG1-itaconate axis in immunomodulation and highlight itaconate and its derivatives as potential therapeutic agents in sepsis.

Keywords

4-OI; CLP; CP: Immunology; IRG1; Itaconate; STING; inflammation; metabolite.

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