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Although the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNF-\u03b1 alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNF-\u03b1 impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism. Using human and murine models of TNF-\u03b1\u2013driven diseases, including myeloproliferative neoplasms and rheumatoid arthritis, we found that TNF-\u03b1 downregulates syntaxin 17 (STX17), a key mediator of autophagosome-lysosome fusion. This disruption inhibited autophagy, leading to the accumulation of dysfunctional mitochondria and reduced mitochondrial respiration. These metabolic alterations compromised platelet-driven clot contraction, a process linked to thrombotic and hemorrhagic complications. Our findings reveal a mechanism by which TNF-\u03b1 disrupts hemostasis through autophagy inhibition, highlighting TNF-\u03b1 as a critical regulator of platelet metabolism and function. This study provides potentially new insights into inflammation-associated pathologies and suggests autophagy-targeting strategies as potential therapeutic avenues to restore hemostatic balance.<\/jats:p>","DOI":"10.1172\/jci186065","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T12:00:26Z","timestamp":1749556826000},"source":"Crossref","is-referenced-by-count":11,"title":["TNF-\u03b1 impairs platelet function by inhibiting autophagy and disrupting metabolism via syntaxin 17 downregulation"],"prefix":"10.1172","volume":"135","author":[{"given":"Guadalupe","family":"Rojas-Sanchez","sequence":"first","affiliation":[{"name":"Bloodworks Research Institute, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Calzada-Martinez","sequence":"additional","affiliation":[{"name":"Bloodworks Research Institute, Seattle, Washington, 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