A novel protein cRERE encoded by a circular RNA directly targets ERK signaling to alleviate chemotherapy-induced neuropathic pain

Jian-Bo Zhang^#¹, Zhong-Bao Zhao^#¹, Jia-Yan Wu^#^{2 3}, Yu-Juan Duan^#^{2 4}, Da-Qiang Zhou², Qiong Li⁵, Xu-Han Ren⁶, Xiao-Hua Yang^{2 7}, Yu-Ting Zhao², Shu-Quan Zhao⁸, Mei-Ying Chen², Xiang-Zhong Zhang⁹, Wen-Jun Xin^{10 11}, Guo-Qing Guo¹², Jing-Dun Xie¹³, Ting Xu¹⁴

Affiliations

¹ Department of Pain Medicine, The Peking University Shenzhen Hospital, Shenzhen, 518036, P. R. China.
² Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-sen University, No. 74, Zhongshan 2nd Road, Guangzhou, 510080, P. R. China.
³ Institute of Neurological Diseases, Shenzhen Bay Laboratory, Gaoke Innovation Center, Shenzhen, 518132, P. R. China.
⁴ Department of Anesthesiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P.R. China.
⁵ Department of Pain Management, People’s Hospital of Longhua, Shenzhen, 518109, P.R. China.
⁶ School of Medicine, Xizang Minzu University, Xianyang, 712082, Shaanxi, P. R. China.
⁷ Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat- sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou, 510060, P. R. China.
⁸ Faculty of Forensic Medicine, Zhongshan Medical School, Sun Yat-sen University, Guangzhou, 510080, P. R. China.
⁹ Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, P. R. China.
¹⁰ Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-sen University, No. 74, Zhongshan 2nd Road, Guangzhou, 510080, P. R. China. xinwj@mail.sysu.edu.cn.
¹¹ School of Medicine, Xizang Minzu University, Xianyang, 712082, Shaanxi, P. R. China. xinwj@mail.sysu.edu.cn.
¹² Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, No. 601, Huangpu Avenue West, Guangzhou, 510630, P. R. China. tgqguo@jnu.edu.cn.
¹³ Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat- sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou, 510060, P. R. China. xiejd6@mail.sysu.edu.cn.
¹⁴ Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-sen University, No. 74, Zhongshan 2nd Road, Guangzhou, 510080, P. R. China. xuting8@mail.sysu.edu.cn.

^# Contributed equally.

PMID: 41107944
PMCID: PMC12535093
DOI: 10.1186/s12964-025-02455-x

Abstract

Circular RNAs (circRNAs), as stable and evolutionarily conserved epigenetic regulators, have attracted growing attention, especially those enriched in the central nervous system (CNS). CNS-specific circRNAs downregulated during disease progression are increasingly recognized as potential therapeutic targets. The clinical translation of circRNAs for stroke treatment further supports the feasibility of circRNA-based therapies, raising the question of whether certain circRNAs may also modulate chemotherapy-induced neuropathic pain (CINP). In this study, we report the identification of a dorsal horn-specific circRere, which is significantly downregulated following vincristine (VCR) administration. Mechanistically, circRere encodes a novel protein, cRERE, in an N6-methyladenosine (m6A)-dependent manner. cRERE alleviates CINP by spatially interfering with the phosphorylation activation site of extracellular signal-regulated kinase 1 (ERK1), thereby preventing downstream activation of the CREB/IL-1β signaling cascade. Taken together, our findings reveal that circRere exerts analgesic effects via an unconventional translation mechanism that generates a functional protein. This study highlights the therapeutic potential of targeting disease-specific downregulated circRNAs and their encoded endogenous proteins for the treatment of CINP.

Keywords: CircRNA; Coding function; Neuropathic pain; Signaling pathway; Spinal dorsal horn.

Cell Commun Signal. 2025 Oct 17;23(1):445.doi: 10.1186/s12964-025-02455-x.(IF:8.9).

A novel protein cRERE encoded by a circular RNA directly targets ERK signaling to alleviate chemotherapy-induced neuropathic pain

Abstract

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