Abstract

Chronic neuropathic pain is a debilitating clinical problem. Sustained activation of satellite glial cells (SGCs) in the dorsal root ganglion (DRG) contributes to neuroinflammation and persistent pain, although the underlying mechanisms driving prolonged SGC activation remain elusive. Here, we report that the non-receptor tyrosine kinase FGR is predominantly increased in DRG SGCs following peripheral nerve injury in mice and macaques. Pharmacological inhibition or genetic knockdown of FGR significantly attenuates SGC activation and pain hypersensitivity. Conversely, mimicking FGR increase in DRG SGCs induces neuroinflammation and neuropathic pain symptoms, largely reversed by NF-κB inhibition. Mechanistically, FGR facilitates p65 phosphorylation by competitively binding p65 at Ser238/240 against phosphatase PP2α. Subsequent nuclear accumulation of hyperphosphorylated p65 directly activates the transcription of Fgr and pro-inflammatory genes, and increased FGR further amplifies p65 phosphorylation. Our findings suggest that FGR is a key player in sustained SGC activation and neuroinflammation and a potential therapeutic target for neuropathic pain.