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

## TL;DR

This study shows that ChREBP reduces neuropathic pain by boosting microglial fatty acid oxidation and anti-inflammatory responses through PGC-1α activation.

## Contribution

The study reveals a novel metabolic-immune axis involving ChREBP and PGC-1α in neuropathic pain regulation.

## Key findings

- ChREBP upregulation in microglia promotes anti-inflammatory responses and fatty acid oxidation.
- PGC-1α transcriptional activation by ChREBP reduces neuroinflammation and pain symptoms.
- Blocking fatty acid oxidation negates the protective effects of ChREBP.

## Abstract

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.

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.

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.

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.

ChREBP transcriptionally regulates PGC‐1α, which enhances the expression of fatty acid oxidation genes, promotes the fatty acid oxidation process, and thereby increases the polarization of anti‐inflammatory microglia, reduces the level of inflammatory factors, and improves pain symptoms.