Artesunate Inhibits Neointimal Hyperplasia by Promoting IRF4 Associated Macrophage Polarization.

Summary

IRF4 is a key regulator of macrophage polarization in restenosis. Genetic manipulation of Irf4 in myeloid cells demonstrated that IRF4 promotes M2 polarization, suppresses M1 transitions, upregulates KLF4, and disrupts macrophage–smooth muscle crosstalk to lessen neointimal hyperplasia. Artesunate, identified as an IRF4 activator, reduced arterial restenosis in both rodent and non-human primate models.

Key Findings

• IRF4 is essential for macrophage polarization in arterial restenosis; myeloid-specific Irf4 loss impairs M2 polarization while overexpression promotes it.
• IRF4 directly upregulates KLF4, suppresses M1 transitions, and disrupts macrophage–vascular smooth muscle cell interactions to reduce neointimal hyperplasia.
• Artesunate was identified as a potent activator of IRF4 in M2 polarization and attenuated restenosis in both rodent and non-human primate models.

Clinical Implications

Supports clinical translation of artesunate as an adjunct to PCI or vascular interventions to reduce restenosis by immunomodulation; highlights IRF4/KLF4 axis as a therapeutic target for vascular healing.

Limitations

• Preclinical study; human dosing, safety, and efficacy remain to be established.
• Long-term effects and interaction with current stent/drug-eluting platforms were not detailed in the abstract.

Future Directions

Early-phase clinical trials of artesunate as an adjunct to PCI; biomarker-guided patient selection leveraging IRF4/KLF4 activity; exploration of combination strategies with anti-proliferative stent drugs.