IGF2BP3 drives macrophage M1 polarization to promote intracranial aneurysm rupture through m6A-mediated NPY1R stabilization.

BACKGROUND: The progression of intracranial aneurysm (IA) was closely associated with an imbalance in M1/M2 macrophage polarization. Neuropeptide Y receptor 1 (NPY1R) was involved in regulating IA development. However, NPY1R in IA-associated macrophages and its impact on macrophage polarization remain to be elucidated. METHODS: Macrophage polarization levels were analyzed by flow cytometry. Molecular expression was detected using RT-qPCR, western blot, and IF assay. Global m⁶A modification levels were measured by colorimetric assay. Cytokine secretion was measured by ELISA. The interaction between Igf2bp3 and Npy1r mRNA was confirmed by RNA pull-down and RIP assays. Pathological changes in cerebral arteries were examined using HE staining. RESULTS: In IA progression, macrophages exhibited increased M1 polarization, accompanied by elevated NPY1R expression and m⁶A modification levels. NPY1R then activated the PI3K/STAT3 pathway to promote macrophage M1 polarization and pro-inflammatory cytokine secretion. Macrophage-specific NPY1R knockout alleviated IA formation and reduced rupture risk by inhibiting M1 polarization. Mechanistically, Igf2bp3 bound to Npy1r mRNA to enhance its stability through m⁶A modification, thereby upregulating Npy1r expression. Igf2bp3 knockdown most effectively decreased Npy1r expression, suppressed M1 polarization, and inactivated the PI3K/STAT3 pathway, whereas NPY1R overexpression reversed these effects. CONCLUSION: IGF2BP3 promoted macrophage M1 polarization and aggravated IA formation by enhancing Npy1r mRNA stability via m⁶A modification to activate the PI3K/STAT3 pathway.