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<p>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 <i>Radx</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月24日

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  • Huifang Xian,
  • Wanming Huang,
  • Zhanghua Chen,
  • Lili Li,
  • Liya Xiong,
  • Jianheng Zhu,
  • Haolan Jin,
  • Xiaotian Li,
  • Lizhi Song,
  • Peiyu Chen,
  • Lu Ren,
  • Wei Wang,
  • Rongli Fang,
  • Xixi Chen,
  • Wen Lei,
  • Dengfeng Zhang,
  • Weiliang Liao,
  • Yuxin Huang,
  • Andrew M Lew,
  • Jun Cui,
  • Sitang Gong,
  • Jun Huang,
  • Jaime S Rosa Duque,
  • Min Zhi,
  • Lanlan Geng,
  • Wenhao Zhou,
  • Yuxia Zhang

摘要

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.