神经性疼痛（NP）的机制被认为是多因素的。细胞因子信号传导抑制因子 1 (SOCS1) 的改变在神经损伤和炎症中发挥着关键作用。人们越来越多地观察到表观遗传 RNA 修饰，特别是 N6-甲基腺苷 (m6A) 甲基化会影响神经系统。然而，目前关于 NP 分子机制中 m6A 甲基化与 SOCS1 之间联系的研究还很少。本研究探讨了 m6A 甲基转移酶样 3 (METTL3) 和 SOCS1 在雌性大鼠脊髓神经结扎 (SNL) 诱导的 NP 中的作用和潜在机制。研究发现，在 NP 中，METTL3 和总体 m6A 水平均下调，导致促炎细胞因子的激活，如白细胞介素 1β、白细胞介素 6 和肿瘤坏死因子 α。值得注意的是，SOCS1 mRNA 显着富集 m6A 甲基化修饰，最常见的 m6A 甲基转移酶 METTL3 通过针对位置 151、164 和 966 处的 m6A 甲基化修饰来稳定 SOCS1 的下调。外源补充 METTL3 可改善 NP 相关的神经炎症和行为功能障碍，但这些影响可以通过 SOCS1 的缺失来逆转。此外，内源性 SOCS1 的消耗通过诱导 Toll 样受体 4 (TLR4) 信号通路促进 NP 进展。 METTL3 的失调以及由此产生的 SOCS1 的 m6A 修饰形成了一个重要的表观遗传调节环，可促进 NP 的进展。以 METTL3/SOCS1 轴为目标可能会为 NP 的潜在治疗策略提供新的见解。版权所有 © 2024。由 Elsevier Ltd 出版。

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.Copyright © 2024. Published by Elsevier Ltd.