miR-15b-5p impairs myelin repair and cognitive recovery after ischemic stroke by targeting the E2F7/CXCL2 axis

Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b-E2F7-CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.