RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity
Genomic instability is increased in patients with inflammatory bowel disease (IBD), yet whether it contributes directly to disease pathogenesis remains unclear. Here, we identify RADX, a structural antagonist to RAD51 and a key regulator of replication fork stability, as a critical suppressor of intestinal inflammation by limiting innate immune sensing of replication-associated DNA damage. RADX deficiency exacerbates experimental colitis, with macrophages serving as the principal mediators of this phenotype. Mechanistically, RADX competes with the DNA sensor IFI16 for binding to single-stranded DNA (ssDNA). Loss of RADX promotes ssDNA accumulation, triggering IFI16-dependent activation of NF-κB signaling and inflammasome assembly, thereby driving intestinal inflammation. Consistent with these findings, two RADX variants identified in patients with IBD associate with reduced RADX protein expression, increased DNA damage signaling, and elevated IL-1β levels. Pharmacological inhibition of RAD51 with RI-1 alleviated colitis in both wild-type and Radx-deficient mice. Together, these findings establish a mechanistic link between genome instability and intestinal inflammation, identify a RADX-IFI16 checkpoint that restrains pathogenic innate immune activation, and nominate modulation of replication stress as a therapeutic strategy for IBD.
Authors
- Wenhao Zhou (ORCID: https://orcid.org/0000-0001-8956-7238)
- Huifang Xian (ORCID: https://orcid.org/0000-0003-1467-2644)
- Zhanghua Chen (ORCID: https://orcid.org/0000-0002-2505-0675)
- Rongli Fang
- Jun Cui (ORCID: https://orcid.org/0000-0002-8000-3708)
- Lanlan Geng (ORCID: https://orcid.org/0000-0002-0336-952X)
- Jun Huang (ORCID: https://orcid.org/0000-0002-7837-653X)
- Wen Lei (ORCID: https://orcid.org/0000-0002-1009-6443)
- Lizhi Song (ORCID: https://orcid.org/0009-0006-2570-7004)
- Wanming Huang
- Min Zhi (ORCID: https://orcid.org/0000-0003-4475-4704)
- Andrew M. Lew (ORCID: https://orcid.org/0000-0002-2198-8164)
- Wei Wang (ORCID: https://orcid.org/0000-0001-6853-7785)
- Peiyu Chen (ORCID: https://orcid.org/0000-0001-7107-2827)
- Xiaotian Li (ORCID: https://orcid.org/0000-0002-2051-4581)
- Haolan Jin
- Yuxia Zhang (ORCID: https://orcid.org/0000-0003-2715-0925)
- Lu Ren (ORCID: https://orcid.org/0000-0001-5730-824X)
- Jianheng Zhu
- X W Chen
- L Y Xiong
- Y Huang (ORCID: https://orcid.org/0009-0005-3406-4875)
- Lili Li
- Jaime S Rosa Duque
- Sitang Gong
- Dengfeng Zhang
- Weiliang Liao (ORCID: https://orcid.org/0009-0002-6677-5215)
Institutions
- Sun Yat-sen University (CN)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Guangzhou Women and Children Medical Center (CN)
- Third Affiliated Hospital of Zhengzhou University (CN)
- Guangzhou Research and Creativity Biotechnology (China) (CN)
- Zhejiang University (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1038/s44321-026-00494-6
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Guangzhou Institute of Pediatrics, Guangzhou Women and Childrens Medical Center
- Guangzhou Municipal Science and Technology Project