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  3. SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice

SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice

  • Nat Commun. 2025 Aug 5;16(1):7225. doi: 10.1038/s41467-025-62565-5.
Yue Huang # 1 2 3,  Gan Ma # 1 2 3,  Shan Xie # 1 2 3,  Runa Wei 1,  Ya Liu 1,  Ying Zeng 1,  Yaxuan Zhao 1,  Qihui Wang 1,  Li Yang 1,  Huiying Huang 1,  Lingyun Hao 1,  Xiaotian Zhao 1,  Hongjun Wang 1,  Wen Shen 1 4,  Stanley Sau Ching Wong 5,  Jun-Li Cao 6 7 8,  Yuan-Xiang Tao 9,  Zhi-Qiang Pan 10 11 12
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, XuzhouMedical University, Xuzhou, Jiangsu, China.
  • 3 National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4 Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5 Department of Anaesthesiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 6 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. caojl0310@aliyun.com.
  • 7 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, XuzhouMedical University, Xuzhou, Jiangsu, China. caojl0310@aliyun.com.
  • 8 National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. caojl0310@aliyun.com.
  • 9 Department of Anesthesiology, New Jersey Medical School, Rutgers. The State University of New Jersey, Novel ark, NJ, USA. yuanxiang.tao@njms.rutgers.edu.
  • 10 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. zhiqiangp2002@aliyun.com.
  • 11 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, XuzhouMedical University, Xuzhou, Jiangsu, China. zhiqiangp2002@aliyun.com.
  • 12 National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China. zhiqiangp2002@aliyun.com.
  • # Contributed equally.
PMID: 40764612 DOI: 10.1038/s41467-025-62565-5
Abstract

Nerve injury-induced changes in pain-associated genes contribute to genesis of neuropathic pain and comorbid anxiety. Phosphorylated CTD interacting factor-1 (PCIF1)-triggered N6, 2'-O-dimethyladenosine (m6Am) mRNA modification represents an additional layer of gene regulation. However, the role of PCIF1 in these disorders is elusive. Here, we report PCIF1 is increased in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex in mouse with neuropathic pain and anxiety, but not inflammatory pain or anxiety alone. Serpine-1 mRNA-binding protein-1 (SERBP1) is identified as a PCIF1 cofactor, their complex mediates m6Am deposition onto mRNA. Blocking SERBP1-PCIF1 upregulation in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex abolishes m6Am gain on maf1 homolog, negative regulator of RNA polymerase III (Maf1), elevates MAF1 protein, and mitigates neuropathic pain and anxiety. Conversely, mimicking this increase adds m6Am onto Maf1, reduces MAF1, and induces comorbidity symptoms. These findings highlight the significance of m6Am in neuropathic pain-anxiety comorbidity and identify SERBP1-PCIF1 in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex as a potential therapeutic target.

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