METTL3-mediated m6A modification of circMtmr7 contributes to paclitaxel-induced peripheral neuropathy in the dorsal horn.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks disease-modifying therapies, and how epitranscriptomic regulation drives central sensitization remains unclear. In the present study focusing on paclitaxel-induced peripheral neuropathy (PIPN), we identified a METTL3-circRNA axis in the spinal dorsal horn wherein upregulated METTL3 expanded the m6A-modified circMtmr7 pool in paclitaxel-treated mice. Accordingly in paclitaxel-treated mice, upregulated METTL3 paralleled elevated m6A-circMtmr7 expression; METTL3 knockdown prevented the paclitaxel-evoked rise in m6A-circMtmr7, normalized miniature excitatory postsynaptic current (EPSC) amplitude and frequency, as well as neuronal firing rates, and alleviated mechanical allodynia. Mechanistically circMtmr7 operated via two convergent branches to upregulate the effector NUFIP2: (i) in the cytoplasm it served as a microRNA (miRNA) sponge for miR-7010-5p, miR-3057-5p and miR-26b-3p, relieving repression and increasing NUFIP2; (ii) in the nucleus it associated with STAT5A to enhance NUFIP2 transcription, and silencing STAT5A reversed neuronal hyperexcitability and attenuated nociceptive behaviours. Genetic or pharmacological manipulation of METTL3, circMtmr7, STAT5A or NUFIP2 bidirectionally modulated neuronal excitability and nociceptive hypersensitivity. Collectively these data establish an m6A-dependent writer-circRNA-transcription factor hub that couples post-transcriptional and transcriptional programmes to amplify excitatory drive in PIPN, suggesting that STAT5A and NUFIP2 represent candidate targets for therapeutic development. KEY POINTS: In paclitaxel-treated mice, spinal dorsal horn METTL3 is upregulated, expanding the m6A-modified circMtmr7 pool to drive central sensitization in paclitaxel-induced peripheral neuropathy. circMtmr7 convergently upregulates NUFIP2 by acting as a cytoplasmic microRNA (miRNA) sponge and by associating with nuclear STAT5A to enhance transcription, thereby amplifying neuronal excitability. Pharmacological or genetic inhibition of METTL3, circMtmr7, STAT5A or NUFIP2 alleviates paclitaxel-induced nociceptive hypersensitivity.