{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:58:41Z","timestamp":1790359121124,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Platelet hyperactivation is the primary driver of thrombosis, which frequently occurs under physiological and pathological hypoxic conditions. Platelet activation is energy-intensive, while it is puzzling to explain hypoxia-associated platelet hyperactivation with energy metabolism. Here, we demonstrate that HIF-1\u03b1-driven glycolytic reprogramming induces platelet hyperactivation by fueling RHOA activation in chronic kidney disease (CKD) and high-altitude cohorts. We show that CKD-associated or hypoxia-induced upregulation of HIF-1\u03b1 stabilizes ADP-dependent glucokinase (ADPGK) by shielding its lysine 125 from ubiquitin-mediated degradation, and ADPGK then utilizes ADP to drive glycolysis, resulting in lactate accumulation in platelets. Subsequently, accumulated lactate induces RHOA lactylation at lysine 7 to enhance its activation, thereby promoting cytoskeletal remodeling and platelet hyperactivation. Pharmacological inhibition of ADPGK with a screened compound Z809269780 effectively alleviates hypoxia-associated platelet hyperactivation and thrombosis. Our findings uncover an unrecognized non-histone lactylation mechanism of platelet hyperactivation and identify a potential therapeutic avenue for hypoxia-induced thrombotic complications.<\/jats:p>","DOI":"10.1182\/blood.2026033745","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:03:36Z","timestamp":1790355816000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["HIF-1\u03b1\/ADPGK-driven glycolytic reprogramming provokes platelet hyperactivation by fueling RHOA lactylation"],"prefix":"10.1182","author":[{"given":"Qigang","family":"Lan","sequence":"first","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhua","family":"Xie","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6107-9088","authenticated-orcid":false,"given":"Baichuan","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuewen","family":"Sun","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Xin","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaozong","family":"Qin","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuiqin","family":"Gong","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangjing","family":"Lv","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xin","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachuan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Yao","sequence":"additional","affiliation":[{"name":"Xinqiao Hospital, Army Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8083-6750","authenticated-orcid":false,"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junping","family":"Wang","sequence":"additional","affiliation":[{"name":"Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,25]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033745\/2591829\/blood.2026033745.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033745\/2591829\/blood.2026033745.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:03:37Z","timestamp":1790355817000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026033745\/571231\/HIF-1-ADPGK-driven-glycolytic-reprogramming"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026033745","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"blood.2026033745"}}