Galectin-9high Neutrophils Exacerbate Radiation-Induced Frailty

  • Aging Cell. 2026 Apr;25(4):e70448. doi: 10.1111/acel.70448.
Zhuo Cheng  1 ,  Le Ma  1 ,  Yan Chen  1 ,  Jialun Li  1 ,  Yali Dai  1 ,  Wentao Xie  1 ,  Yingjie Li  1 ,  Tianlang Xu  1 ,  Zhihe Hu  1 ,  Weilin Huang  1 ,  Jingyuan Zhou  1 ,  Jie Wu  1 ,  Long Chen  1 ,  Chunmeng Shi  1
Affiliations
  • 1. Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China.
PMID: 41947008 DOI: 10.1111/acel.70448
Abstract

Local radiation injury-induced frailty seriously impacts the quality of life of patients undergoing radiotherapy or nuclear accident casualties and causes a significant medical and economic burden. However, the underlying mechanisms of the frailty remain unknown. In this study, a unique population of hyperactive GAL-9high neutrophils is identified with characteristics of elevated ROS, NETs, and IFN-γ, prolonged lifespan, etc. These neutrophils infiltrate into multiple organs to induce injuries, also disrupt the bone marrow microenvironment, drive sustained bone marrow myeloid-biased differentiation, and resist clearance by bone marrow macrophages, serving as a crucial factor to exacerbate frailty. GAL-9 protein is demonstrated to play a vital role in the regulation of neutrophil hyperactivity. EccDNA shedding after skin radiation injury is shown to activate the JAK1/2-STAT1 pathway in splenic GMP cells, which is a potential origin of GAL-9high neutrophils. In summary, our results highlight the significance of the previously unrecognized hyperactive GAL-9high neutrophils to exacerbate frailty through a 'skin-spleen-bone marrow-multiple organs' axis after local radiation injury.

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