2. Academic Validation
  3. PGC-1α Transcriptionally Regulated by ChREBP Mitigates Neuropathic Pain Through Promoting Microglial Fatty Acid Oxidation and Anti-Inflammatory Response

PGC-1α Transcriptionally Regulated by ChREBP Mitigates Neuropathic Pain Through Promoting Microglial Fatty Acid Oxidation and Anti-Inflammatory Response

  • CNS Neurosci Ther. 2026 Jan;32(1):e70744. doi: 10.1002/cns.70744.
Ziwei Hu 1 2 3 4,  Jiahui Pang 1,  Xinli Liu 1,  Yun Zhao 1,  Yi Lu 5,  Hui Chen 1,  Hui Zeng 1,  Youxin Yu 1,  Yubai Zhao 6,  Lijie Gao 1,  Xuefei Zhang 1,  Jian Jin 1,  Kangling Wang 1,  Yu Shi 1,  Hongrui Zhan 7,  Wen Wu 1 2 3 4
Affiliations

Affiliations

  • 1 Center of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 2 School of Rehabilitation Sciences, Southern Medical University, Guangzhou, China.
  • 3 Guang Dong Engineering Technology Research Center of Brain Function Assessment and Neuroregulation Rehabilitation, Guangzhou, China.
  • 4 Institute of Exercise and Rehabilitation Science, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 5 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 6 Department of Clinical and Rehabilitation Medicine, Guiyang Healthcare Vocational University, Guizhou, China.
  • 7 Department of Rehabilitation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
PMID: 41517974 DOI: 10.1002/cns.70744
Abstract

Background: Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progression. Although ChREBP (key metabolic regulator) protects against NP, its specific mechanisms remain unclear.

Methods: NP rat model was established via spared nerve injury (SNI) surgery, and mechanical allodynia was evaluated using Von Frey tests. ChREBP expression in microglia was detected through immunofluorescence, RT-qPCR, and western blot. Functional studies involved ChREBP knockdown/overexpression to assess effects on microglial polarization, neuroinflammation, neuronal excitability, pain behaviors, and fatty acid metabolism. Mechanisms were explored via dual-luciferase reporter and chromatin immunoprecipitation assays.

Results: Mechanical pain thresholds were significantly decreased on the ipsilateral side after SNI. ChREBP was upregulated in SDH microglia after SNI and in LPS-stimulated microglia in vitro. ChREBP knockdown inhibited anti-inflammatory microglial polarization, exacerbated neuroinflammation, and aggravated pain. Conversely, ChREBP overexpression promoted the anti-inflammatory phenotype, suppressed neuroinflammation, and alleviated pain. ChREBP enhanced microglial fatty acid oxidation and energy metabolism. Mechanistically, ChREBP bound to the TFBS1 site on the PGC-1α promoter to activate its transcription. PGC-1α overexpression rescued the impairments caused by ChREBP knockdown, including reduced fatty acid oxidation, suppressed anti-inflammatory polarization, elevated inflammatory factors, and increased neuronal excitability. The protective effects of ChREBP were attenuated by the fatty acid oxidation inhibitor Etomoxir.

Conclusions: ChREBP alleviates NP by enhancing microglial fatty acid oxidation and anti-inflammatory phenotype via PGC-1α transcriptional activation, revealing a novel metabolic-immune axis for potential NP therapy.

Keywords

ChREBP; PGC‐1α; fatty acid oxidation; microglia; neuropathic pain.

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