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Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from\n            <jats:italic>Hylarana guentheri<\/jats:italic>\n            skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in\u00a0vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in\u00a0vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in\u00a0vivo in a FeCl\n            <jats:sub>3<\/jats:sub>\n            injury-induced carotid artery model. The results showed that Cath-HG exhibited an \u03b1-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In\u00a0vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations\/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.\n          <\/jats:p>","DOI":"10.34133\/research.0381","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T16:45:37Z","timestamp":1713285937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":21,"title":["Cathelicidin-HG Alleviates Sepsis-Induced Platelet Dysfunction by Inhibiting GPVI-Mediated Platelet Activation"],"prefix":"10.34133","volume":"7","author":[{"given":"Weichen","family":"Xiong","sequence":"first","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Chai","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiena","family":"Wu","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Li","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wancheng","family":"Lu","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maolin","family":"Tian","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, \rSouthern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Amine","family":"Jmel","sequence":"additional","affiliation":[{"name":"Institute of Parasitology, \rBiology Centre of the Czech Academy of Sciences, Branisovska 31, Budweis (Ceske Budejovice) 37005, Czech Republic."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes H.","family":"Ippel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), \rMaastricht University, 6229 ER Maastricht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Kotsyfakis","sequence":"additional","affiliation":[{"name":"Institute of Parasitology, \rBiology Centre of the Czech Academy of Sciences, Branisovska 31, Budweis (Ceske Budejovice) 37005, Czech Republic."},{"name":"Institute of Molecular Biology and Biotechnology, \rFoundation for Research and Technology-Hellas, 70013 Heraklion, Crete, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Dijkgraaf","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht 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