2. Academic Validation
  3. FOXA2 regulated by HDAC3-mediated deacetylation attenuates neuropathic pain by modulating microglial lipid metabolism and synaptic pruning dysregulation

FOXA2 regulated by HDAC3-mediated deacetylation attenuates neuropathic pain by modulating microglial lipid metabolism and synaptic pruning dysregulation

  • J Neuroinflammation. 2025 Nov 26;22(1):280. doi: 10.1186/s12974-025-03601-5.
Hui Zeng # 1,  Bo Wang # 1 2,  ZhiLin Huang # 3,  LiJie Gao 1,  Yao Xiao 4,  XinLi Liu 1,  Yin Xu 1,  ZiWei Hu 1,  JiaHui Pang 1,  YouXin Yu 1,  YanWu Guo 5,  Wen Wu 6 7
Affiliations

Affiliations

  • 1 Center of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 2 Department of Rehabilitation, Tongji Medical College, Traditional Chinese and Western Medicine Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Neurosurgery, The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Southern Medical University, Guangzhou, 510282, China.
  • 4 Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 5 Department of Neurosurgery, The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Southern Medical University, Guangzhou, 510282, China. [email protected].
  • 6 Center of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China. [email protected].
  • 7 School of Rehabilitation Sciences, Southern Medical University, Guangzhou, 510282, China. [email protected].
  • # Contributed equally.
PMID: 41299504 DOI: 10.1186/s12974-025-03601-5
Abstract

Background: Persistent neuroinflammation and synaptic dysregulation in the spinal dorsal horn (SDH) has been well-established as a critical mechanism contributing to neuropathic pain (NP). Microglia play a pivotal role in modulating both neuroinflammatory responses and synaptic pruning. While metabolic disturbances are known to significantly impact microglial functionality, the precise mechanistic relationship remains poorly understood.

Methods: This study seeks to elucidate how FOXA2-mediated regulation of lipid metabolism influences microglial function. Multiple assays were conducted on mouse SDH tissues and in vitro microglial cells, including immunofluorescence, transmission electron microscopy (TEM), qRT-PCR, Western blot (WB), and specific indicator assay kits, to comprehensively evaluate: (i) microglial lipid metabolism, (ii) mitochondrial morphology and functional integrity, (iii) inflammatory cytokine levels, and (iv) synaptic phagocytic activity. AAV-mediated FOXA2 overexpression or knockdown was employed to investigate its therapeutic effects on NP via modulating microglial lipid metabolism homeostasis. Transcriptome Sequencing analysis, Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were employed to investigate the regulatory mechanisms among HDAC3, CPT1A, and FOXA2.

Results: Here we demonstrate that both spared nerve injury (SNI) and lipopolysaccharide (LPS) stimulation trigger significant lipid droplet accumulation and mitochondrial dysfunction in microglia, leading to impaired phagocytic function. FOXA2 ameliorates NP by upregulating CPT1A to restore microglial lipid metabolism and mitochondrial homeostasis, thereby meliorating dysregulated synaptic pruning and alleviating neuroinflammation. We identified HDAC3-mediated deacetylation as a critical regulatory mechanism controlling FOXA2 transcriptional activity. Pharmacological inhibition of HDAC3 by RGFP966 significantly enhanced FOXA2 binding to the CPT1A promoter region, thereby amplifying FOXA2-dependent lipid metabolic reprogramming in microglia.

Conclusions: Collectively, our study establishes microglial lipid metabolism as a critical regulator of NP pathogenesis, orchestrating both neuroinflammatory responses and synaptic remodeling processes. These findings unveil novel therapeutic opportunities for pain management through targeted modulation of microglial metabolic homeostasis.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03601-5.

Keywords

FOXA2; Lipid metabolism; Microglia; Neuropathic pain; Synaptic pruning.

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