Mevalonate Metabolism Orchestrates Platelet Hyperactivation via Protein Prenylation to Aggravate Septic Thrombosis

Abstract

Sepsis is a life-threatening systemic inflammatory disorder that triggers disseminated intravascular coagulation and microthrombosis, in which exaggerated platelet activation exacerbates disease progression. The mevalonate pathway is responsible for the biosynthesis of vital isoprenoids and sterols, also playing an important role in the prenylation modification of proteins. We found the mevalonate metabolic pathway is highly activated in platelets during infection. The interruption of this pathway, using platelet specific mevalonate kinase deficiency mice model, could significantly suppress platelet activation and NETosis, alleviating sepsis-induced intravascular thrombosis. Mechanistically, we identified prenylated proteins in platelets and found prenylation level of small GTPases, such as Rap1, were increased after sepsis, indicating the important role of protein prenylation in platelet hyperactivation during sepsis. Notably, the binding level of Rap1 and Talin-1 was significantly impaired in MVK deficient platelets, showing that Rap1-Talin-1 interaction is crucial for MVA-mediated platelet activation. Furthermore, as inhibitors of prenyl diphosphate synthase, the lipophilic bisphosphonates TH-Z145 and TH-Z93 exerted potent effects in alleviating platelet activation and septic thrombosis, as well as prolonging survival in sepsis mice. Collectively, targeting the MVA pathway provides a novel therapeutic strategy for sepsis-triggered thrombosis and platelet activation.