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

Yue Huang, Gan Ma, Shan Xie, Runa Wei, Ya Liu, Ying Zeng, Yaxuan Zhao, Qihui Wang, Li Yang, Huiying Huang, Lingyun Hao, Xiaotian Zhao, Hongjun Wang, Wen Shen, Stanley Sau Ching Wong, Jun-Li Cao (), Yuan-Xiang Tao () and Zhi-Qiang Pan ()
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Yue Huang: Xuzhou Medical University
Gan Ma: Xuzhou Medical University
Shan Xie: Xuzhou Medical University
Runa Wei: Xuzhou Medical University
Ya Liu: Xuzhou Medical University
Ying Zeng: Xuzhou Medical University
Yaxuan Zhao: Xuzhou Medical University
Qihui Wang: Xuzhou Medical University
Li Yang: Xuzhou Medical University
Huiying Huang: Xuzhou Medical University
Lingyun Hao: Xuzhou Medical University
Xiaotian Zhao: Xuzhou Medical University
Hongjun Wang: Xuzhou Medical University
Wen Shen: Xuzhou Medical University
Stanley Sau Ching Wong: The University of Hong Kong
Jun-Li Cao: Xuzhou Medical University
Yuan-Xiang Tao: Rutgers. The State University of New Jersey
Zhi-Qiang Pan: Xuzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62565-5

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