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<p>Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS–STING innate immune pathway to drive the SASP. We identify the exportin-1 (XPO1)–DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.</p>

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Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Xue Hao,
  • Bo Zhao,
  • Qingqing Yan,
  • Mitsutake Yano,
  • Ayumu Matsuoka,
  • Yuan Qi,
  • Liping Liao,
  • Rafal J. Zielinski,
  • Hsin-Yao Tang,
  • Andrew V. Kossenkov,
  • M. Anna Zal,
  • Kavitha Sarma,
  • Rugang Zhang

摘要

Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS–STING innate immune pathway to drive the SASP. We identify the exportin-1 (XPO1)–DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.