Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity–associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K⁺ channel promoter, thereby causing K⁺ channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K⁺ channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K⁺ channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain.

许多表观遗传调节因子与疼痛相关的脊柱可塑性有关。共激活剂相关精氨酸甲基转移酶 1 (CARM1) 是组蛋白精氨酸甲基化的表观遗传调节因子，是神经可塑性中非常有趣的靶标。然而，它对脊柱可塑性相关的神经性疼痛发展的潜在贡献仍然缺乏探索。在这里，我们报告神经损伤降低了脊髓 CARM1 的表达并诱发异常性疼痛。此外，Fbxo3介导的CARM1泛素化降低脊髓CARM1表达促进K ⁺通道启动子处的H3R17me2减少，从而导致K ⁺通道表观遗传沉默和神经性疼痛的发生。值得注意的是，在幼稚大鼠中，使用 CARM1 siRNA 或 CARM1 抑制剂减少脊髓 CARM1 会导致类似的表观遗传信号和异常性疼痛。此外，鞘内注射 BC-1215（一种新型 Fbxo3 抑制剂）可防止 CARM1 泛素化，从而阻断 K ⁺通道基因沉默并改善神经损伤后的异常性疼痛。总的来说，结果表明，这种新发现的脊髓 Fbxo3-CARM1-K ⁺通道基因功能轴可促进神经性疼痛。这些发现提供了重要的见解，将有助于开发更有效和更具体的神经性疼痛疗法。