IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.

Summary

This mechanistic study shows that IRAP drives lysosomal degradation of ribosomes (ribophagy) in activated platelets during septic thrombosis, supplying amino acids to glycolysis to sustain energy-intensive activation. Blocking IRAP reduces platelet hyperactivation and septic thrombosis, nominating IRAP as a druggable node linking immunothrombosis and metabolism.

Key Findings

• IRAP promotes lysosomal degradation of ribosomes (ribophagy) in activated platelets via mTORC1- and S-acylation–dependent mechanisms.
• Amino acids liberated by ribophagy fuel aerobic glycolysis, reprogramming platelet energy metabolism to sustain activation.
• Pharmacologic or targeted blockade of IRAP attenuates platelet hyperactivation and reduces septic thrombosis.

Clinical Implications

While preclinical, targeting IRAP could offer a novel adjunct to reduce septic immunothrombosis without broadly suppressing host defenses; translational work and safety profiling are needed.

Limitations

• Preclinical study without validation in human clinical cohorts.
• Potential off-target or compensatory pathways were not fully excluded; safety profile of IRAP inhibition is unknown.

Future Directions

Validate IRAP–ribophagy signatures in human sepsis, develop selective IRAP inhibitors/biologics with favorable PK/PD and safety, and test efficacy in sepsis models reflecting clinical heterogeneity.