RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity

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

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;
Details: Publication Year 2026-09,Volume 18,Issue #9,Page 3570-3596
Journal Title: EMBO Molecular Medicine
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-kappaB 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-1beta 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
Keywords: Animals; *Immunity, Innate; *Nuclear Proteins/metabolism/immunology; *Phosphoproteins/metabolism/immunology; Mice; Humans; *Colitis/pathology/immunology/genetics; Mice, Knockout; Rad51 Recombinase/metabolism/antagonists & inhibitors; *Inflammatory Bowel Diseases/immunology/pathology/genetics; DNA Damage; DNA, Single-Stranded/metabolism; Macrophages/immunology; DNA-Binding Proteins/metabolism; Mice, Inbred C57BL; NF-kappa B/metabolism; Inflammation
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: 2026-09-14 09:09:13