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<p>Sepsis triggers profound organism-wide disturbances, yet the cellular logic underlying its systemic impact remains poorly defined. By integrating single-cell transcriptomes from six septic tissues, we uncovered a conserved cross-tissue program characterized by inflammation-driven senescence, disrupted intercellular communication, and coordinated transcriptional reprogramming. Senescence signatures were broadly elevated across cell types and strongly coupled to altered communication networks, suggesting that septic stress induces both cell-intrinsic and network-level remodeling. We identified several key transcription factors, with activation of Atf4, Cebpb and Cebpd, alongside repression of Foxo1, Gata4, and Yy1, which might rewire inflammatory and stress-adaptive programs toward senescence-like states. Endothelial and neutrophil populations were inferred to act as the principal amplifiers of this response through predicted Cxcl1-Cxcr2 and Cxcl2-Ackr1 circuits, potentially establishing self-reinforcing inflammatory-senescent loops. Finally, the neutrophil-derived signature serves as a robust molecular adjunct to traditional clinical metrics, significantly improving risk stratification and enhancing the prognostic accuracy for sepsis patients. Together, our findings position sepsis as a potent driver of accelerated immunological aging and provide conserved regulatory mechanisms that may represent therapeutic targets for mitigating both acute injury and long-term sequelae.</p>

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Systemic mapping of senescence characteristics across septic tissues

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Chen Zhou,
  • Yunmeng Bai

摘要

Sepsis triggers profound organism-wide disturbances, yet the cellular logic underlying its systemic impact remains poorly defined. By integrating single-cell transcriptomes from six septic tissues, we uncovered a conserved cross-tissue program characterized by inflammation-driven senescence, disrupted intercellular communication, and coordinated transcriptional reprogramming. Senescence signatures were broadly elevated across cell types and strongly coupled to altered communication networks, suggesting that septic stress induces both cell-intrinsic and network-level remodeling. We identified several key transcription factors, with activation of Atf4, Cebpb and Cebpd, alongside repression of Foxo1, Gata4, and Yy1, which might rewire inflammatory and stress-adaptive programs toward senescence-like states. Endothelial and neutrophil populations were inferred to act as the principal amplifiers of this response through predicted Cxcl1-Cxcr2 and Cxcl2-Ackr1 circuits, potentially establishing self-reinforcing inflammatory-senescent loops. Finally, the neutrophil-derived signature serves as a robust molecular adjunct to traditional clinical metrics, significantly improving risk stratification and enhancing the prognostic accuracy for sepsis patients. Together, our findings position sepsis as a potent driver of accelerated immunological aging and provide conserved regulatory mechanisms that may represent therapeutic targets for mitigating both acute injury and long-term sequelae.