RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity
- Author(s)
- Xian, H; Huang, W; Chen, Z; Li, L; Xiong, L; Zhu, J; Jin, H; Li, X; Song, L; Chen, P; Ren, L; Wang, W; Fang, R; Chen, X; Lei, W; Zhang, D; Liao, W; Huang, Y; Lew, AM; Cui, J; Gong, S; Huang, J; Rosa Duque, JS; Zhi, M; Geng, L; Zhou, W; Zhang, Y;
- Journal Title
- EMBO Molecular Medicine
- Publication Type
- Jul 24
- Abstract
- 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.
- Publisher
- Springer
- Research Division(s)
- Immunology
- PubMed ID
- 42498843
- Publisher's Version
- https://doi.org/10.1038/s44321-026-00494-6
- Open Access at Publisher's Site
https://doi.org/10.1038/s44321-026-00494-6- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-07-30 09:25:13
Last Modified: 2026-07-30 09:25:28