HIF-1α/ADPGK驱动的糖酵解重编程通过促进RHOA乳酰化引发血小板过度活化
HIF-1α/ADPGK-driven glycolytic reprogramming provokes platelet hyperactivation by fueling RHOA lactylation
血小板过度活化是血栓形成的主要驱动力，常发生在缺氧状态下，但缺氧为何导致血小板活化一直令人困惑。研究在慢性肾病和高海拔人群中发现，缺氧稳定HIF-1α，进而保护ADPGK蛋白不被降解；ADPGK利用ADP驱动糖酵解，使血小板内乳酸堆积。乳酸进一步使RHOA蛋白第7位赖氨酸发生乳酰化，增强其活化，促进细胞骨架重塑和血小板过度活化。用一种筛选出的化合物Z809269780抑制ADPGK，可有效缓解缺氧相关血小板活化和血栓。这揭示了一种新的非组蛋白乳酰化机制，并提示潜在治疗靶点，但尚处临床前阶段。
为什么推荐给您：发现血小板活化新机制并提出可干预靶点，但证据限于体外与临床前，未进入人体。
不需要生物学背景，多打比方
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摘要Abstract
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-1α-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-1α 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.