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Updated: Aug 21, 2026
Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
METTL3-mediated m6A modification of circMtmr7 contributes to paclitaxel-induced peripheral neuropathy in the dorsal
Chaopeng Ou1, Zhaoli He1,2, Sudena Wang1
1Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Abstract:
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.
Insights
Chemotherapy-induced peripheral neuropathy (CIPN) lacks treatments. This study reveals how METTL3 and circMtmr7 in the spinal cord amplify pain signals, identifying STAT5A and NUFIP2 as potential therapeutic targets for CIPN.
Area of Science:
- Neuroscience
- Molecular Biology
- Oncology
Background:
- Chemotherapy-induced peripheral neuropathy (CIPN) presents a significant clinical challenge with limited disease-modifying therapies.
- The underlying mechanisms of epitranscriptomic regulation in central sensitization during CIPN remain incompletely understood.
Purpose of the Study:
- To elucidate the role of the METTL3-circRNA axis in paclitaxel-induced peripheral neuropathy (PIPN).
- To investigate the downstream pathways involving circMtmr7, STAT5A, and NUFIP2 in mediating neuronal hyperexcitability and nociception.
Main Methods:
- Utilized a mouse model of paclitaxel-induced peripheral neuropathy (PIPN).
- Investigated the expression and function of METTL3, circMtmr7, STAT5A, and NUFIP2 in the spinal dorsal horn.
- Employed techniques including gene knockdown, miRNA sponge assays, and assessment of neuronal excitability and behavioral nociceptive responses.
Main Results:
- Upregulated METTL3 expanded the m6A-modified circMtmr7 pool in the spinal dorsal horn of paclitaxel-treated mice.
- circMtmr7 enhanced NUFIP2 expression via cytoplasmic miRNA sponging and nuclear STAT5A association.
- METTL3 knockdown or inhibition of circMtmr7, STAT5A, or NUFIP2 alleviated mechanical allodynia and normalized neuronal excitability.
Conclusions:
- Established an m6A-dependent METTL3-circRNA-STAT5A-NUFIP2 axis that amplifies excitatory drive in PIPN.
- This axis couples post-transcriptional and transcriptional regulation to drive central sensitization.
- STAT5A and NUFIP2 are identified as promising therapeutic targets for managing CIPN.
