Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China; The First Clinical College of Guangxi University of Traditional Chinese Medicine, Nanning, China.
The First Clinical College of Guangxi University of Traditional Chinese Medicine, Nanning, China.
Neuropharmacology. 2024 Dec 15;261:110176. doi: 10.1016/j.neuropharm.2024.110176. Epub 2024 Sep 30.
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.
神经病理性疼痛（NP）的机制被认为是多因素的。细胞因子信号转导抑制因子 1（SOCS1）的改变在神经损伤和炎症中起着关键作用。越来越多的研究观察到表观遗传 RNA 修饰，特别是 N6-甲基腺苷（m6A）甲基化，对神经系统有影响。然而，关于 m6A 甲基化与 SOCS1 在 NP 分子机制中的联系的研究还很少。本研究探讨了 m6A 甲基转移酶样 3（METTL3）和 SOCS1 在脊神经结扎（SNL）诱导的 NP 雌性大鼠中的作用及其潜在机制。研究发现，在 NP 中，METTL3 和整体 m6A 水平均下调，导致促炎细胞因子如白细胞介素 1β、白细胞介素 6 和肿瘤坏死因子-α的激活。值得注意的是，SOCS1 mRNA 明显富含 m6A 甲基化修饰，最常见的 m6A 甲基转移酶 METTL3 通过靶向 m6A 甲基化修饰位置 151、164 和 966 稳定 SOCS1 的下调。外源性补充 METTL3 可改善 NP 相关的神经炎症和行为功能障碍，但 SOCS1 的缺失可逆转这些效应。此外，内源性 SOCS1 的耗竭通过诱导 Toll 样受体 4（TLR4）信号通路促进 NP 的进展。METTL3 的失调和 SOCS1 的相应 m6A 修饰形成了一个关键的表观遗传调节环，促进了 NP 的进展。针对 METTL3/SOCS1 轴可能为 NP 的潜在治疗策略提供新的思路。
