4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Costimulation with ICM and ICMA led to a partial reversal in CD86 expression even without zinc ions, potentially due to the ability of 4-OI to modulate macrophage polarization via alkylating cysteine sites of STING.
“However, it was noteworthy that Fig. 4G revealed that costimulation with ICM and ICMA led to a partial reversal in CD86 expression although there were no zinc ions, potentially due to the ability of 4-OI to modulate macrophage polarization via alkylating cysteine sites of STING (39).”
From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [39]
Cites
Molecular mechanisms and cellular functions of cGAS–STING signalling
Hopfner, K.-P., & Hornung, V. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0244-x · Cited by 2,052 · see citing works
Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685792 · Cited by 526 · see citing works
Olagnier, D., Brandtoft, A. M., Gunderstofte, C., Villadsen, N. L., Krapp, C., Thielke, A. L., Laustsen, A., Peri, S., Hansen, A. L., Bonefeld, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05861-7 · Cited by 282 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Han, H., Yu, D., Liu, Y., Jia, H., & Liu, W. (2025) · Science Advances · doi:10.1126/sciadv.adz4126 · Cited by 7 · see citing works
“4G revealed that costimulation with ICM and ICMA led to a partial reversal in CD86 expression although there were no zinc ions, potentially due to the ability of 4-OI to modulate macrophage polarization via alkylating cysteine sites of STING ( 39 ).”
- Authors
- Li, W., Li, Y., Kang, J., Jiang, H., Gong, W., Chen, L., Wu, C., Liu, M., Wu, X., Zhao, Y., & Ren, J.
- Affiliations
- Anhui University of Science and Technology (CN)
- Nanjing General Hospital of Nanjing Military Command (CN)
- Nanjing Medical University (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Corresponding author
- Wu, Xiuwen
- Zhao, Yun
- Ren, Jianan
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 42
- Issue
- 3
- Pages
- 112145
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4322622043
- Cited by
- 117
- References
- 3
- Citations by year
- 2026: 32 · 2025: 45 · 2024: 29 · 2023: 11
- FWCI
- 12.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82072223, 82072149, 82272237, 82272209)
- Jiangsu Provincial Key Research and Development Program (BE2022823)
- Jiangsu Provincial Commission of Health and Family Planning (ZDB2020028)
- Natural Science Foundation of Jiangsu Province (BK20201116)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- 4-octyl itaconate, itaconate, STING, IRG1, alkylation, cysteine modification, STING phosphorylation, sepsis, inflammation, macrophages, immunometabolism, immunomodulation
- MeSH terms
- Alkylation, Humans, Inflammation, Membrane Proteins, Proteins, Succinates
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
