FASN regulates STING palmitoylation via malonyl-CoA in macrophages to alleviate sepsis-induced liver injury

  • Biochim Biophys Acta Mol Basis Dis. 2024 Jun 13;1870(7):167299. doi: 10.1016/j.bbadis.2024.167299.
Jiaqi Kang  1 ,  Jie Wu  2 ,  Qinjie Liu  3 ,  Haiyang Jiang  4 ,  Weizhen Li  5 ,  Yangguang Li  1 ,  Xuanheng Li  1 ,  Chujun Ni  6 ,  Lei Wu  7 ,  Mingda Liu  8 ,  Haiqing Liu  6 ,  Liting Deng  9 ,  Zexing Lin  4 ,  Xiuwen Wu  10 ,  Yun Zhao  11 ,  Jianan Ren  12
Affiliations
  • 1. Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China.
  • 2. Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, PR China; Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, PR China.
  • 3. Department of General Surgery, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, PR China.
  • 4. Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, PR China.
  • 5. Department of Emergency Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, PR China.
  • 6. Surgical Research Laboratory, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, PR China.
  • 7. Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, PR China.
  • 8. The Core Laboratory, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, PR China.
  • 9. Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 10. Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China. Electronic address: [email protected].
  • 11. Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, PR China. Electronic address: [email protected].
  • 12. Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China. Electronic address: [email protected].
PMID: 38878833 DOI: 10.1016/j.bbadis.2024.167299
Abstract

STING (stimulator of interferon genes) is a critical immunoregulatory protein in sepsis and is regulated by various mechanisms, especially palmitoylation. FASN (fatty acid synthase) is the rate-limiting enzyme to generate cellular palmitic acid (PA) via acetyl-CoA and malonyl-CoA and participates in protein palmitoylation. However, the mechanisms underlying the interaction between STING and FASN have not been completely understood. In this study, STING-knockout mice were used to confirm the pivotal role of STING in sepsis-induced liver injury. Metabolomics confirmed the dyslipidemia in septic mice and patients. The compounds library was screened, revealing that FASN inhibitors exerted a significant inhibitory effect on the STING pathway. Mechanically, the regulatory effect of FASN on the STING pathway was dependent on palmitoylation. Further experiments indicated that the upstream of FASN, malonyl-CoA inhibited STING pathway possibly due to C91 (palmitoylated residue) of STING. Overall, this study reveals a novel paradigm of STING regulation and provides a new perspective on immunity and metabolism.

Keywords
FASN; Macrophages; Malonyl-CoA; STING.
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