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

## TL;DR

A circular RNA called circRere produces a protein that reduces chemotherapy-induced nerve pain by blocking a key signaling pathway.

## Contribution

The study identifies a novel protein, cRERE, encoded by circRere, which alleviates neuropathic pain through a unique mechanism.

## Key findings

- circRere is downregulated in the spinal cord after chemotherapy with vincristine.
- cRERE inhibits ERK1 phosphorylation, preventing the activation of the CREB/IL-1β signaling cascade.
- The protein is produced via an m6A-dependent translation mechanism, offering a new therapeutic strategy for neuropathic pain.

## 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.

The online version contains supplementary material available at 10.1186/s12964-025-02455-x.