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

Summary

This translational mechanistic study demonstrated that the platelet mevalonate pathway is activated during sepsis and promotes platelet hyperactivation through protein prenylation, including enhanced Rap1-Talin-1 interaction. Platelet-specific mevalonate kinase deficiency and the prenyl diphosphate synthase inhibitors TH-Z145 and TH-Z93 reduced platelet activation, neutrophil extracellular trap formation, septic thrombosis, and mortality in mice.

Key Findings

• The mevalonate pathway was highly activated in platelets during infection.
• Platelet-specific mevalonate kinase deficiency reduced platelet activation, neutrophil extracellular trap formation, and sepsis-induced intravascular thrombosis.
• TH-Z145 and TH-Z93 reduced platelet activation and septic thrombosis and prolonged survival in septic mice.
• Rap1 prenylation and Rap1-Talin-1 interaction were implicated as downstream mechanisms.

Clinical Implications

The findings support further development of mevalonate-pathway or prenylation inhibitors for septic thrombosis, but they do not justify clinical use because efficacy and safety have only been demonstrated in experimental models. Future translation must address bleeding risk, immune effects, infection clearance, and optimal treatment timing.

Limitations

• The evidence is based on experimental sepsis models, and the number and characteristics of animals are not provided in the abstract.
• The translational safety profile, including bleeding and effects on host defense, remains unresolved.

Future Directions

Independent validation in multiple sepsis models, dose-ranging and pharmacokinetic studies, assessment of bleeding and antimicrobial-host-defense effects, and eventual early-phase clinical trials are needed. Biomarkers of platelet mevalonate-pathway activation could help identify patients most likely to benefit.