Peripheral nerve injury-induced upregulation of acyl-CoA synthetase 2 contributes to neuropathic pain via mediating microglial autophagy disruption in the spinal dorsal horn.

Authors

Yiming Qiao, Liren Li, Liying Bai, Yan Gao, Xueli Wang, Lili Yv, Haozhuang Yuan, Sailong Wei, Ji-Tian Xu

Published in

Brain, behavior, and immunity. Pages 106914. Jul 12, 2026. Epub Jul 12, 2026.

Abstract

Acyl-CoA synthetase 2 (ACSS2), by producing acetyl-coenzyme A from acetate in the nucleus, facilitates histone acetylation and regulates gene expression. However, the role of ACSS2 in neuropathic pain remains unclear. Herein, we found that lumbar 5 spinal nerve ligation (SNL) increased ACSS2 expression predominately in microglia of the spinal dorsal horn. This increase was accompanied by elevated histone H3K27 acetylation (H3K27ac), enhanced raptor expression, activated mTORC1/TFEB signaling, raised p62, and reduced LC3II/LC3I ratio. Repeated intrathecal or intravenous injections of ACSS2 inhibitor (ACSS2i) partially prevented development of, and reversed established, neuropathic pain in male and female rats. Microglia-specific AAV-F4/80-ACSS2 shRNA injection into L5 spinal dorsal horn alleviated SNL-induced pain hypersensitivity, counteracted the increase in H3K27ac and rescued mTORC1/TFEB signaling-mediated autophagy impairment. SNL-enhanced binding of SP1, a transcriptional regulator of raptor, and the elevation of H3K27ac at the raptor promoter were inhibited by AAV-F4/80-ACSS2 shRNA. The increases of IL-1β and TNF-α production after SNL were also reversed by these interventions. Microglia-specific Acss2 knockout (Acss2^cKO) mitigated SNL-induced abnormal pain, and prevented microglial autophagy disruption in male and female mice. ACSS2i treatment decreased H3K27ac, reduced SP1 binding with raptor promoter, and restored autophagy disruption in cultured BV2 cells following LPS stimulation. In addition, knockdown of ACSS2 specifically in neurons or astrocytes partially reduced pain following SNL. Collectively, our findings suggest that the peripheral nerve injury-induced upregulation of ACSS2 in the spinal dorsal horn contributes to neuropathic pain might partially through regulating raptor expression and subsequently activating mTORC1/TFEB signaling-mediated microglial autophagy disruption.

PMID:
42437581
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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