HIF-1α/ADPGK-driven glycolytic reprogramming provokes platelet hyperactivation by fueling RHOA lactylation.

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.