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Peer-reviewedCC BY-NC-NDBiomarker Research

Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives

  • Lizhou Song1,2,3
  • Tian Zhou1,3
  • Yue Shu1,2,3
  • Jibo Zhao4
  • Yan Liao1,3
  • Chenglong Zhu1,3
  • Haoling Zhang5
  • Wangzheqi Zhang6,7
  • Zui Zou8,9
9 affiliations
  1. 1Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
  2. 2School of Anesthesiology, Hebei North University, Hebei, 075000, China
  3. 3School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
  4. 4Department of Anesthesiology, the First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, 075000, China
  5. 5Department of Biomedical Sciences, Cancer Research and Specialist Centre, Universiti Sains Malaysia, Penang, 13200, Malaysia. [email protected]
  6. 6Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. [email protected]
  7. 7School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China. [email protected]
  8. 8Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. [email protected]
  9. 9School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China. [email protected]
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Abstract

Neutrophil extracellular traps (NETs) are chromatin-based extracellular structures consisting of DNA, histones and multiple antimicrobial proteins, which exert dual biological effects in host defense and inflammation-triggered tissue injury. This review focuses on NET-associated signaling pathways and their regulatory crosstalk with diverse forms of regulated cell death (RCD) in inflammatory disorders. First, we summarize the structural characteristics and biogenesis pathways of NETs closely linked to inflammatory amplification, including lytic and non-lytic NETosis as well as reactive oxygen species (ROS)-dependent and ROS-independent mechanisms, and elaborate the functions of NADPH oxidase, myeloperoxidase, neutrophil elastase, peptidylarginine deiminase 4 and gasdermin D during these processes. Second, we discuss how NET-derived damage-associated molecular patterns, such as DNA, histones, granular proteases, ROS and mitochondrial DNA, interact with apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis. Under pathological conditions, excessive NET formation or impaired NET clearance leads to autoantigen exposure, accelerated thrombosis, enhanced inflammasome activation, parenchymal cell damage and modulated tumor progression. Finally, we outline therapeutic interventions targeting NET biogenesis, NET clearance and downstream NETs-driven signaling, with an emphasis on the translational potential and safety concerns of these strategies across distinct diseases. Future investigations are required to decipher context-dependent NETs-RCD regulatory circuits, standardize NETs detection protocols, and develop precision-targeted therapeutics that restrain pathological inflammation while preserving host antimicrobial defense.

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Cite

BibTeXRIS
BibTeX
@article{song2026cell,
  title = {{Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives}},
  author = {Lizhou Song and Tian Zhou and Yue Shu and Jibo Zhao and Yan Liao and Chenglong Zhu and Haoling Zhang and Wangzheqi Zhang and Zui Zou},
  journal = {Biomarker Research},
  year = {2026},
  month = jun,
  doi = {10.1186/s40364-026-00959-3},
  url = {https://doi.org/10.1186/s40364-026-00959-3},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives
AU  - Lizhou Song
AU  - Tian Zhou
AU  - Yue Shu
AU  - Jibo Zhao
AU  - Yan Liao
AU  - Chenglong Zhu
AU  - Haoling Zhang
AU  - Wangzheqi Zhang
AU  - Zui Zou
PY  - 2026
DA  - 2026/06/24
JO  - Biomarker Research
DO  - 10.1186/s40364-026-00959-3
UR  - https://doi.org/10.1186/s40364-026-00959-3
AB  - Neutrophil extracellular traps (NETs) are chromatin-based extracellular structures consisting of DNA, histones and multiple antimicrobial proteins, which exert dual biological effects in host defense and inflammation-triggered tissue injury. This review focuses on NET-associated signaling pathways and their regulatory crosstalk with diverse forms of regulated cell death (RCD) in inflammatory disorders. First, we summarize the structural characteristics and biogenesis pathways of NETs closely linked to inflammatory amplification, including lytic and non-lytic NETosis as well as reactive oxygen species (ROS)-dependent and ROS-independent mechanisms, and elaborate the functions of NADPH oxidase, myeloperoxidase, neutrophil elastase, peptidylarginine deiminase 4 and gasdermin D during these processes. Second, we discuss how NET-derived damage-associated molecular patterns, such as DNA, histones, granular proteases, ROS and mitochondrial DNA, interact with apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis. Under pathological conditions, excessive NET formation or impaired NET clearance leads to autoantigen exposure, accelerated thrombosis, enhanced inflammasome activation, parenchymal cell damage and modulated tumor progression. Finally, we outline therapeutic interventions targeting NET biogenesis, NET clearance and downstream NETs-driven signaling, with an emphasis on the translational potential and safety concerns of these strategies across distinct diseases. Future investigations are required to decipher context-dependent NETs-RCD regulatory circuits, standardize NETs detection protocols, and develop precision-targeted therapeutics that restrain pathological inflammation while preserving host antimicrobial defense.
SN  - 2050-7771
ER  -