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<p>The effective treatment of neuropathic pain continues to be a major clinical hurdle, largely because its pathogenic mechanisms are incompletely defined. This study identifies Fgr kinase as a central player in governing autophagy within spinal microglia during the development of neuropathic pain. Using a rat model of chronic constriction injury (CCI), we found that damage to peripheral nerves causes a prolonged increase in Fgr expression specifically in microglia of the spinal dorsal horn (SDH). Genetic interventions and behavioral analyses demonstrated that Fgr overexpression induced pain symptoms, whereas Fgr knockdown alleviated pain hypersensitivity. Mechanistically, Fgr directly phosphorylated STAT3, promoting its nuclear translocation and suppressing autophagic flux, evidenced by reduced LC3-II/LC3-I ratio, accumulated SQSTM1, and diminished autophagosomes. Pharmacological inhibition of Fgr by intrathecal TL02-59 (10 μg/kg) restored autophagy, attenuated STAT3 activation, and reversed CCI-induced neuropathic pain behaviors. These findings position the Fgr–STAT3 axis as a tractable target to normalize microglial autophagy and alleviate neuropathic pain.</p>

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Targeting Fgr-STAT3 Mediated Autophagy Inhibition in the Spinal Cord Alleviates Neuropathic Pain in Rats

  • 期刊论文

  • 发表日期：

    2026年4月9日

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  • Liqiong He,
  • Yu Zhang,
  • Chunguang Yang,
  • Zhifeng Huang,
  • Kailu Zou,
  • Qingwei Deng,
  • Jianxi Zhang,
  • Malijiang Mulati,
  • Bei Sun,
  • Qulian Guo,
  • Changsheng Huang

摘要

The effective treatment of neuropathic pain continues to be a major clinical hurdle, largely because its pathogenic mechanisms are incompletely defined. This study identifies Fgr kinase as a central player in governing autophagy within spinal microglia during the development of neuropathic pain. Using a rat model of chronic constriction injury (CCI), we found that damage to peripheral nerves causes a prolonged increase in Fgr expression specifically in microglia of the spinal dorsal horn (SDH). Genetic interventions and behavioral analyses demonstrated that Fgr overexpression induced pain symptoms, whereas Fgr knockdown alleviated pain hypersensitivity. Mechanistically, Fgr directly phosphorylated STAT3, promoting its nuclear translocation and suppressing autophagic flux, evidenced by reduced LC3-II/LC3-I ratio, accumulated SQSTM1, and diminished autophagosomes. Pharmacological inhibition of Fgr by intrathecal TL02-59 (10 μg/kg) restored autophagy, attenuated STAT3 activation, and reversed CCI-induced neuropathic pain behaviors. These findings position the Fgr–STAT3 axis as a tractable target to normalize microglial autophagy and alleviate neuropathic pain.