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

  • Nat Aging. 2026 Jun;6(6):1208-1226. doi: 10.1038/s43587-026-01147-6.
Xue Hao  1 ,  Bo Zhao  2  3 ,  Qingqing Yan  4  5  6 ,  Mitsutake Yano  1 ,  Ayumu Matsuoka  1 ,  Yuan Qi  7 ,  Liping Liao  1 ,  Rafal J Zielinski  1 ,  Hsin-Yao Tang  8 ,  Andrew V Kossenkov  4 ,  M Anna Zal  9 ,  Kavitha Sarma  4 ,  Rugang Zhang  10
Affiliations
  • 1. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 3. Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
  • 5. Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences, Shenzhen, China.
  • 6. State Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 7. Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 9. Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
PMID: 42303864 DOI: 10.1038/s43587-026-01147-6
Abstract

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.

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