2. Academic Validation
  3. PCIF1-mediated m6Am modification in ACC neurons participates in inflammatory pain and anxiety

PCIF1-mediated m6Am modification in ACC neurons participates in inflammatory pain and anxiety

  • Cell Rep. 2026 Mar 24;45(3):117016. doi: 10.1016/j.celrep.2026.117016.
Ya Liu 1,  Yue Huang 2,  Keqing Xue 2,  Gan Ma 2,  Shan Xie 2,  Yaxuan Zhao 2,  Ying Zeng 2,  Shuangshuang Li 3,  Li Yang 2,  Lingyun Hao 2,  Xiaotian Zhao 2,  Hongjun Wang 2,  Qihui Wang 4,  Cunjin Wang 5,  Zhiqiang Pan 6
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Northern Jiangsu People's Hospital, The Yangzhou Clinical Medical College of Xuzhou Medical University, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 3 Department of Anesthesiology, Eye & ENT Hospital of Fudan University, No. 83, Fenyang Road, Shanghai 200031, China.
  • 4 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: [email protected].
  • 5 Northern Jiangsu People's Hospital, The Yangzhou Clinical Medical College of Xuzhou Medical University, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China. Electronic address: [email protected].
  • 6 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: [email protected].
PMID: 41712381 DOI: 10.1016/j.celrep.2026.117016
Abstract

N6,2'-O-dimethyladenosine (m6Am) modification, mediated by the methyltransferase phosphorylated CTD interacting factor 1 (PCIF1), is increasingly recognized as an important layer of gene regulation. However, the role of m6Am in pain and comorbid anxiety has not yet been explored. Here, we report that persistent peripheral inflammation reduces PCIF1 levels in the mouse anterior cingulate cortex (ACC). This downregulation is triggered by decreased binding of GLI2 to the Pcif1 promoter. Knocking out or conditionally deleting Pcif1 in ACC neurons reduces the m6Am level of Gap43 mRNA, leading to the increased expression of GAP43 and pre-long-term potentiation (LTP) oversaturation, which in turn results in inflammatory pain and its comorbid anxiety-like behavior. Conversely, knocking down GAP43 suppresses the pre-LTP oversaturation caused by PCIF1 reduction, thereby alleviating inflammatory pain and comorbid anxiety. This study reveals a mechanism whereby GLI2-governed PCIF1 contributes to the modulation of inflammatory pain and comorbid anxiety through the targeting of Gap43 m6Am in the ACC.

Keywords

CP: neuroscience; GAP43; PCIF1; anterior cingulate cortex; inflammatory pain and comorbid anxiety; m(6)Am modification.

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