2. Academic Validation
  3. A positive feedback loop between FGR and p65 sustains satellite glial cell activation and chronic neuropathic pain

A positive feedback loop between FGR and p65 sustains satellite glial cell activation and chronic neuropathic pain

  • Cell Rep. 2026 Feb 24;45(2):116899. doi: 10.1016/j.celrep.2025.116899.
Yangyuxin Huang 1,  Yanni He 1,  Zanbing Wang 1,  Fan Zhang 1,  Meiling Han 1,  Xinying Guo 2,  Yuqiong Xie 3,  Junwu Wang 1,  Xiaotian Ma 1,  Jia Dan 1,  Yutao Deng 1,  Hongming Wu 1,  Hao Hu 1,  Jingkai Wang 4,  Lina Yu 5,  Bao-Chun Jiang 6,  Min Yan 7,  Longfei Ma 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou 310009, China.
  • 2 Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou 510623, China.
  • 3 Center for Basic and Translational Research, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 4 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou 310009, China.
  • 5 Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou 310009, China. Electronic address: [email protected].
  • 6 Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou 310009, China. Electronic address: [email protected].
  • 7 Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou 310009, China. Electronic address: [email protected].
  • 8 Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou 310009, China. Electronic address: [email protected].
PMID: 41575848 DOI: 10.1016/j.celrep.2025.116899
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.

Keywords

CP: molecular biology; CP: neuroscience; FGR; dorsal root ganglion; neuroinflammation; neuropathic pain; satellite glial cells.

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