4-octyl itaconate inhibits cytokine-mediated inflammation via alkylation of TYK2 and JAK1

  • Cell Rep. 2026 Mar 30;45(4):117179. doi: 10.1016/j.celrep.2026.117179.
Weizhen Li  1 ,  Qiong Zhang  2 ,  Songqi Jing  3 ,  Liting Deng  4 ,  Haiyang Jiang  5 ,  Jinpeng Zhang  3 ,  Zhiwu Hong  3 ,  Zherui Zhang  3 ,  Shuai Hao  3 ,  Lei Wu  3 ,  Tao Zheng  6 ,  Yilong Yu  6 ,  Xiao Ma  7 ,  Xuefeng Wang  7 ,  Qingchuan Li  8 ,  Zhentao Yu  8 ,  Mingda Liu  9 ,  Jiaxin Yang  7 ,  Bin Liu  3 ,  Haiqing Liu  5 ,  Chujun Ni  5 ,  Cunxia Wu  5 ,  Zitian Hu  10 ,  Pengfei Zheng  11 ,  Peige Wang  12 ,  Yun Zhao  13 ,  Jianan Ren  14 ,  Xiuwen Wu  15
Affiliations
  • 1. Medical Department of Qingdao University, Qingdao 266000, China; Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China.
  • 2. Department of Obstetrics and Gynecology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China.
  • 3. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China.
  • 4. Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing 210000, China.
  • 5. Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 6. The First People's Hospital of Shanghai, Shanghai 200000, China.
  • 7. Medical Department of Qingdao University, Qingdao 266000, China.
  • 8. School of Medicine, Anhui University of Science and Technology, Huainan 232000, China.
  • 9. The Core Laboratory, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.
  • 10. College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 11. College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].
  • 12. Medical Department of Qingdao University, Qingdao 266000, China. Electronic address: [email protected].
  • 13. Department of General Surgery, Clinical Translational Research Center for Surgical Infection and Immunity, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China. Electronic address: [email protected].
  • 14. Medical Department of Qingdao University, Qingdao 266000, China; Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China. Electronic address: [email protected].
  • 15. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China. Electronic address: [email protected].
PMID: 41915469 DOI: 10.1016/j.celrep.2026.117179
Abstract

Itaconate is a Krebs cycle-derived metabolite whose production is catalyzed by immune response gene 1 (IRG1). As an anti-inflammatory metabolite, itaconate primarily exerts its effects through alkylation of target proteins. Previous studies have identified the JAK-STAT pathway as a key therapeutic target in sepsis. Interestingly, we report that itaconate, a metabolite significantly upregulated during metabolic reprogramming, suppresses type I interferon (IFN-I) signaling. Exogenous supplementation with the itaconate derivative 4-octyl itaconate (4OI) inhibits the JAK-STAT pathway. Mechanistically, 4OI inhibits the binding of tyrosine kinase 2 (Tyk2) to IFNAR1 and JAK1 to IFNAR2 by alkylating cysteine 192 in Tyk2 and cysteine 189 in JAK1. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid (TCA) cycle in restricting JAK-STAT signal transduction, thereby linking metabolism and innate immunity, and provides a theoretical basis for the therapeutic application of 4OI in sepsis.

Keywords
4-octyl itaconate; CP: immunology; CP: metabolism; IFN-I; IRG1; JAK1; TYK2; inflammation; itaconate; sepsis.
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