2. Academic Validation
  3. A20 attenuates oxidized self-DNA-mediated inflammation in acute kidney injury

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

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. drguoyq@wchscu.cn.
  • 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. pingzhang68@hotmail.com.
  • 10 Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. sklbshaobin@scu.edu.cn.
  • 11 Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. sklbshaobin@scu.edu.cn.
  • # 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.

Figures
Products