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Peer-reviewedCC BYNature communications

Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.

  • Jingyi Zhou1,2
  • Xinyi Ma3
  • Bing Jiang2,3
  • Zisheng Fan2
  • Penghua Li1,4
  • Qi Dai1,2,5
  • Yajie Wang1,2,5
  • Min Wu2,6
  • Qibang Sui7
  • Ning Ma1,2,5
  • Ruirui Yang1,5
  • Haiwei Shen1,5
7 more authors
  • Jingyi Meng3
  • Manlin Huang2,6
  • Zhiming Ge1,2,5
  • Jiusheng Lin1,5
  • Dan Teng8,9
  • Mingyue Zheng10,11,12,13,14
  • Sulin Zhang15,16,17
17 affiliations
  1. 1School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  2. 2Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  3. 3School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  4. 4Department of Translational Medicine Platform, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
  5. 5University of Chinese Academy of Sciences, Beijing, China.
  6. 6School of Pharmacy, Nanchang University, Nanchang, China.
  7. 7Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
  8. 8Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  9. 9University of Chinese Academy of Sciences, Beijing, China. [email protected].
  10. 10School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  11. 11Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  12. 12School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  13. 13University of Chinese Academy of Sciences, Beijing, China. [email protected].
  14. 14School of Pharmacy, Nanchang University, Nanchang, China. [email protected].
  15. 15School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  16. 16Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  17. 17University of Chinese Academy of Sciences, Beijing, China. [email protected].
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Abstract

Aberrant activation of the STING signaling pathway is involved with aging-related inflammation, yet no STING-targeting therapeutics are clinically approved. Here, we identify Omaveloxolone, an FDA-approved drug for Friedreich's ataxia, as a potent STING degrader (DC₅₀ = 118 nM, Dmax = 98.6%) via high-throughput screening. Omaveloxolone binds non-covalently to the base of the STING ligand-binding domain (LBD) with high affinity (KD = 21.4 nM) and exhibits crowbar-like behavior consistent with STING conformational destabilization: it hinders LBD closure, increases hydrophobic exposure, and reduces thermal stability. This conformational perturbation is proposed to enhance recognition by the E3 ubiquitin ligase HUWE1, leading to K27-linked ubiquitination at STING lysines K236/K347/K370 and proteasomal degradation. In vivo, Omaveloxolone depletes STING, suppresses downstream inflammatory signaling, and ameliorates aging-related inflammatory phenotypes in aged male mice. Because Omaveloxolone is also an established NRF2 activator, these in vivo benefits likely reflect dual modulation of inflammatory and antioxidant pathways. This study implicates Omaveloxolone as a molecular crowbar-like STING degrader and provides a mechanistic framework for targeting STING via conformational perturbation.

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Cite

BibTeXRIS
BibTeX
@article{zhou2026omaveloxolone,
  title = {{Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.}},
  author = {Jingyi Zhou and Xinyi Ma and Bing Jiang and Zisheng Fan and Penghua Li and Qi Dai and Yajie Wang and Min Wu and Qibang Sui and Ning Ma and Ruirui Yang and Haiwei Shen and Jingyi Meng and Manlin Huang and Zhiming Ge and Jiusheng Lin and Dan Teng and Mingyue Zheng and Sulin Zhang},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77760-1},
  url = {https://europepmc.org/article/MED/42957659},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.
AU  - Jingyi Zhou
AU  - Xinyi Ma
AU  - Bing Jiang
AU  - Zisheng Fan
AU  - Penghua Li
AU  - Qi Dai
AU  - Yajie Wang
AU  - Min Wu
AU  - Qibang Sui
AU  - Ning Ma
AU  - Ruirui Yang
AU  - Haiwei Shen
AU  - Jingyi Meng
AU  - Manlin Huang
AU  - Zhiming Ge
AU  - Jiusheng Lin
AU  - Dan Teng
AU  - Mingyue Zheng
AU  - Sulin Zhang
PY  - 2026
DA  - 2026/09/17
JO  - Nature communications
DO  - 10.1038/s41467-026-77760-1
UR  - https://europepmc.org/article/MED/42957659
AB  - Aberrant activation of the STING signaling pathway is involved with aging-related inflammation, yet no STING-targeting therapeutics are clinically approved. Here, we identify Omaveloxolone, an FDA-approved drug for Friedreich's ataxia, as a potent STING degrader (DC₅₀ = 118 nM, Dmax = 98.6%) via high-throughput screening. Omaveloxolone binds non-covalently to the base of the STING ligand-binding domain (LBD) with high affinity (KD = 21.4 nM) and exhibits crowbar-like behavior consistent with STING conformational destabilization: it hinders LBD closure, increases hydrophobic exposure, and reduces thermal stability. This conformational perturbation is proposed to enhance recognition by the E3 ubiquitin ligase HUWE1, leading to K27-linked ubiquitination at STING lysines K236/K347/K370 and proteasomal degradation. In vivo, Omaveloxolone depletes STING, suppresses downstream inflammatory signaling, and ameliorates aging-related inflammatory phenotypes in aged male mice. Because Omaveloxolone is also an established NRF2 activator, these in vivo benefits likely reflect dual modulation of inflammatory and antioxidant pathways. This study implicates Omaveloxolone as a molecular crowbar-like STING degrader and provides a mechanistic framework for targeting STING via conformational perturbation.
SN  - 2041-1723
ER  -