2. Academic Validation
  3. IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1

IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1

  • Cell Rep. 2025 Sep 26;44(10):116336. doi: 10.1016/j.celrep.2025.116336.
Li Chai 1,  Chaoqun Li 2,  Xuefeng Wang 3,  Yanyang Qin 4,  Hemin Sun 2,  Jie Du 2,  Liu Yang 2,  Dongmei Hu 5,  Jianan Xiong 1,  Zhiyuan Zhao 2,  Rong Gong 2,  Tao Wu 2,  Meng Wu 6,  Meng Nie 7,  Jialin Gao 8,  Jihui Jia 2,  Chengjiang Gao 1,  Wei Zhao 2,  Huan Zhou 9,  Dongwei Kang 10,  Mutian Jia 11
Affiliations

Affiliations

  • 1 Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Key Laboratory for Experimental Teratology of Ministry of Education, Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • 4 Key Laboratory of Chemical Biology (Ministry of Education) & Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, China.
  • 5 Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 6 Department of Cell Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 7 School of Public Health, Capital Medical University, Beijing 100069, China.
  • 8 Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241002, China.
  • 9 National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Clinical Research Hospital of The First Affiliated Hospital of Anhui Medical University, Hefei, China; Key Laboratory of Innovative Drug Pharmaceutical Research and Clinical Evaluation Jointly Established Disciplines in Anhui Province, Hefei, China. Electronic address: zhouhuan@bbmc.edu.cn.
  • 10 Key Laboratory of Chemical Biology (Ministry of Education) & Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, China. Electronic address: kangdongwei@sdu.edu.cn.
  • 11 Key Laboratory of Infection Immunity and Disease Intervention of Shandong Province, Key Laboratory for Experimental Teratology of Ministry of Education, Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: jmt@sdu.edu.cn.
PMID: 41014555 DOI: 10.1016/j.celrep.2025.116336
Abstract

Perturbation of energy metabolism is an essential feature during Infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral Infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral Infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.

Keywords

CP: Immunology; IRG1; TBK1; antiviral immune response; energy metabolism; itaconic acid.

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