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Here, we identify a key role for platelet\u2010released heat shock protein 90\u03b1 (HSP90\u03b1) 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 HSP90\u03b1, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90\u03b1 to their plasma membrane and release it into the extracellular space in both free and exosome\u2010associated forms. Extracellular HSP90\u03b1 acts as a damage\u2010associated molecular pattern that binds to toll\u2010like receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88\u2013Beclin 1 signaling pathway, triggering autophagy and leading to NET formation. Blocking extracellular HSP90\u03b1 with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis\u2010related thrombosis and inflammation. This platelet\u2013HSP90\u03b1\u2013TLR4\u2013autophagy\u2013NET pathway not only deepens our understanding of platelet\u2010induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.<\/jats:p>","DOI":"10.1002\/advs.202515933","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:05:23Z","timestamp":1773003923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Activated Platelet\u2013Released Heat Shock Protein 90\u03b1 Triggers Autophagy\u2010Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis"],"prefix":"10.1002","volume":"13","author":[{"given":"Chengbo","family":"Wang","sequence":"first","affiliation":[{"name":"Henan Clinical Research Center of Childhood Diseases Henan Key Laboratory of Children's Genetics and Metabolic Diseases Henan Children's Hospital Zhengzhou 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