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

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.