A20 attenuates oxidized self-DNA-mediated inflammation in acute kidney injury

  • Signal Transduct Target Ther. 2025 Apr 25;10(1):154. doi: 10.1038/s41392-025-02194-y.
Hanwen Li  #  1 ,  Yongyao Wu  #  1 ,  Lisha Xiang  #  2 ,  Qing Zhao  #  1 ,  Lu Liu  3 ,  Zhixiong Zhu  4 ,  Weimin Lin  1 ,  Zhan Li  5 ,  Yang Yang  4 ,  Yiting Ze  1 ,  Lulu Zhang  6 ,  Ping Fu  7 ,  Yingqiang Guo  8 ,  Ping Zhang  9 ,  Bin Shao  10  11
Affiliations
  • 1. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, PR China.
  • 2. Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
  • 3. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR China.
  • 4. Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
  • 5. Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, PR China.
  • 6. College of Foreign Languages and Cultures, Sichuan University. Sichuan University, Chengdu, Sichuan, PR China.
  • 7. Kidney Research Institute, National Clinical Research Center for Geriatrics and Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China.
  • 8. Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. [email protected].
  • 9. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, PR China. [email protected].
  • 10. Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. [email protected].
  • 11. Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. [email protected].
  • # Contributed equally.
PMID: 40280946 DOI: 10.1038/s41392-025-02194-y
Abstract

The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis, but its role in self-DNA-mediated inflammation in acute kidney injury (AKI) is not well understood. Here, our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients. This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome. While inhibition of the STING pathway only slightly attenuates AKI progression, suppression of NLRP3 inflammasome-mediated Pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice. Subsequently, we found that Tnfaip3 (encoding A20) is significantly upregulated following oxidized self-DNA treatment. A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated Pyroptosis. Moreover, A20-derived peptide (P-II) also significantly alleviates ox-dsDNA-induced Pyroptosis and improves the survival and renal injury of AKI mice. Mechanistically, A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome. A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7. Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex. Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models. This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.

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