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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\u2013specific 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-1\u03b2 signaling cascade. 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This study highlights the therapeutic potential of targeting disease-specific downregulated circRNAs and their encoded endogenous proteins for the treatment of CINP.<\/jats:p>","DOI":"10.1186\/s12964-025-02455-x","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:55:39Z","timestamp":1760702139000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel protein cRERE encoded by a circular RNA directly targets ERK signaling to alleviate chemotherapy-induced neuropathic pain"],"prefix":"10.1186","volume":"23","author":[{"given":"Jian-Bo","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong-Bao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Yan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Juan","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-Qiang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-Han","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Hua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Ting","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Quan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Zhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Jun","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Qing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-Dun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"2455_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14030612","author":"A Uittenboogaard","year":"2022","unstructured":"Uittenboogaard A, Neutel CLG, Ket JCF, Njuguna F, Huitema ADR, Kaspers GJL, et al. 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