2. Academic Validation
  3. Activated Platelet-Released Heat Shock Protein 90α Triggers Autophagy-Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis

Activated Platelet-Released Heat Shock Protein 90α Triggers Autophagy-Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis

  • Adv Sci (Weinh). 2026 May;13(25):e15933. doi: 10.1002/advs.202515933.
Chengbo Wang 1,  Maodong Leng 2,  Chenchen Sun 3,  Jingyu Cao 1,  Linfei Li 1,  Yangyang Jia 1,  Yongshuai Han 1,  Yuchun Liu 1,  Yaodong Zhang 1,  Chenglong Zhang 4,  Yingli Men 5,  Ningyuan Liu 6,  Yibing Cheng 7,  Yixia Zhang 1,  Ya Li 8,  Zhenlong Li 9,  Lidan Cui 7,  Xiangzhan Zhu 1 10
Affiliations

Affiliations

  • 1 Henan Clinical Research Center of Childhood Diseases, Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
  • 2 Reproductive Medicine Center, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Department of Head and Neck Surgery, Anyang Tumor Hospital Affiliated to Henan University of Science and Technology, Anyang Tumor Hospital, Anyang, Henan, China.
  • 4 School of Life Science, Henan Institute of Science and Technology, Xinxiang, China.
  • 5 Translational Medicine Research Center, Zhengzhou People's Hospital, The Fifth Clinical College of Henan University of Chinese Medicine, Zhengzhou, China.
  • 6 Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 7 Zhengzhou Children's Hospital PICU, Henan Children's Hospital, Zhengzhou Children's Hospital, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
  • 8 Henan Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 9 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California, USA.
  • 10 School of Life Sciences, Zhengzhou University, Zhengzhou, China.
PMID: 41732887 DOI: 10.1002/advs.202515933
Abstract

Platelets are crucial to the development of thrombosis and coagulation abnormalities in sepsis, but the mechanisms by which they contribute to these pathological processes are not fully understood. Here, we identify a key role for platelet-released heat shock protein 90α (HSP90α) in driving neutrophil extracellular trap (NET) formation and supporting thromboinflammation during sepsis. Proteomic analysis of platelets from patients with sepsis showed a significant increase in HSP90α, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90α to their plasma membrane and release it into the extracellular space in both free and exosome-associated forms. Extracellular HSP90α acts as a damage-associated molecular pattern that binds to Toll-like Receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88-Beclin 1 signaling pathway, triggering Autophagy and leading to NET formation. Blocking extracellular HSP90α with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis-related thrombosis and inflammation. This platelet-HSP90α-TLR4-autophagy-NET pathway not only deepens our understanding of platelet-induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.

Keywords

HSP90α; NET; autophagy; platelet; sepsis.

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