Inhibition of histone deacetylase 6 alleviates neuropathic pain via direct regulating post-translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis

J Neuroinflammation. 2025 Mar 11;22(1):74. doi: 10.1186/s12974-025-03400-y.

Abstract

Neuropathic pain, a debilitating nerve injury-induced condition, remains a significant clinical challenge. This study evaluates the effect of histone deacetylase 6 (HDAC6) inhibition in a spared nerve injury (SNI) mouse model. Systemic administration of the selective HDAC6 inhibitor ACY-1215 (20 mg/kg/day, 14 days), alleviated SNI-induced pain in mice of both sexes. ACY-1215 increased acetylated signal transducer and activator of transcription 3 (Ac-STAT3) and reduced phosphorylated STAT3 (p-STAT3) in the lumbar spinal cord of SNI mice. HDAC6 and p-STAT3 were expressed in spinal dorsal horn neurons, and SNI-enhanced HDAC6/STAT3 interaction was reversed by ACY-1215. Neuronal STAT3 overexpression induced pain hypersensitivity and elevated p-STAT3, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), effects suppressed by ACY-1215. Cytokine profiling identified CC-chemokine ligand 7 (CCL7) as a key downstream effector of the HDAC6/STAT3 axis, with ACY-1215 attenuating SNI-induced CCL7 upregulation. HDAC6 knockdown in neurons reduced p-STAT3, while HDAC6 or STAT3 knockdown diminished CCL7 production. These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management.

Keywords: ACY-1215; CCL7; HDAC6; Neuropathic pain; STAT3.

MeSH terms

  • Animals
  • Female
  • Histone Deacetylase 6* / antagonists & inhibitors
  • Histone Deacetylase 6* / metabolism
  • Histone Deacetylase Inhibitors* / pharmacology
  • Histone Deacetylase Inhibitors* / therapeutic use
  • Hydroxamic Acids* / pharmacology
  • Hydroxamic Acids* / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia* / drug therapy
  • Neuralgia* / metabolism
  • Pyrimidines
  • STAT3 Transcription Factor* / metabolism
  • Spinal Cord* / drug effects
  • Spinal Cord* / metabolism

Substances

  • STAT3 Transcription Factor
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Stat3 protein, mouse
  • Hdac6 protein, mouse
  • ricolinostat
  • Pyrimidines