FGF17 synergistically targets neuronal survival and oligodendrogenesis to restore stroke deficits.

Stroke remains a leading cause of long-term disability, and recovery is often limited by impaired neurorestoration and glial scar-mediated inhibition of axonal regeneration. Although fibroblast growth factor 17 (FGF17) regulates oligodendrocyte plasticity during aging, its therapeutic potential and underlying mechanisms in ischemic stroke remain unclear. We investigated whether FGF17 could promote functional recovery by enhancing neuronal restoration and overcoming glial scar-associated inhibition. Fgf17-positive cell distribution was mapped using Fgf17-reporter mice (Fgf17CreERT2/+;Rosa-CAG-LSL-tdTomato). Focal ischemia was induced in the motor cortex and anterior cingulate cortex of wild-type and Fgf17-deficient (Fgf17-/-) mice via photothrombosis. Recombinant FGF17 was administered intranasally. Functional recovery was evaluated using motor and cognitive behavioral tests. Mechanistic studies were performed using viral tracing, immunofluorescence, and molecular assays focusing on the extracellular signal-regulated kinase (Erk)-serum response factor (SRF) and phospholipase C gamma (PLCγ)-cyclic adenosine monophosphate (cAMP) signaling pathways. FGF17 was predominantly expressed in neurons, whereas its receptor, fibroblast growth factor receptor 3 (FGFR3), was widely distributed. Fgf17-/- mice exhibited larger infarcts and more severe functional deficits, whereas intranasal FGF17 significantly improved motor and cognitive outcomes in both wild-type and knockout mice. Mechanistically, FGF17 promoted oligodendrogenesis and myelin repair by upregulating SRF through the Erk signaling pathway. Concurrently, FGF17 activated the PLCγ-adenylyl cyclase axis, increased intracellular cAMP levels, and enabled axonal regeneration within the inhibitory microenvironment through downregulation of mRNA levels of oligodendrocyte myelin glycoprotein, neurite outgrowth inhibitor A, and myelin-associated glycoprotein. In addition, FGF17 enhanced neuronal survival and preserved dendritic spines via the PI3K-Akt pathway. Overall, FGF17 promotes oligodendrogenesis and enhances the intrinsic regenerative capacity of neurons. These findings identify FGF17 signaling as a promising therapeutic target for neurorestoration after stroke.