Liu Tengfei, Huang Gan, Guo Xin, Ji Qiuran, Yu Lu, Zong Runzhe, Li Yiquan, Song Xiaomeng, Fu Qingyi, Xue Qidi, Zheng Yi, Zeng Fanshuo, Sun Ru, Chen Lin, Gao Chengjiang, Liu Huiqing
Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
Acta Pharm Sin B. 2025 Aug;15(8):4014-4029. doi: 10.1016/j.apsb.2025.06.005. Epub 2025 Jun 9.
Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in regulating the necroptosis and apoptosis in cerebral ischemia-reperfusion (I/R) injury. However, the regulation of RIPK1 kinase activity after cerebral I/R injury remains largely unknown. In this study, we found the downregulation of protein arginine methyltransferase 1 (PRMT1) was induced by cerebral I/R injury, which negatively correlated with the activation of RIPK1. Mechanistically, we proved that PRMT1 directly interacted with RIPK1 and catalyzed its asymmetric dimethylarginine, which then blocked RIPK1 homodimerization and suppressed its kinase activity. Moreover, pharmacological inhibition or genetic ablation of PRMT1 aggravated I/R injury by promoting RIPK1-mediated necroptosis and apoptosis, while PRMT1 overexpression protected against I/R injury by suppressing RIPK1 activation. Our findings revealed the molecular regulation of RIPK1 activation and demonstrated PRMT1 would be a potential therapeutic target for the treatment of ischemic stroke.
受体相互作用蛋白激酶1（RIPK1）在调节脑缺血再灌注（I/R）损伤中的坏死性凋亡和凋亡过程中起着至关重要的作用。然而，脑I/R损伤后RIPK1激酶活性的调节在很大程度上仍不清楚。在本研究中，我们发现脑I/R损伤可诱导蛋白质精氨酸甲基转移酶1（PRMT1）表达下调，且其与RIPK1的激活呈负相关。机制上，我们证明PRMT1直接与RIPK1相互作用并催化其不对称二甲基精氨酸化，进而阻止RIPK1同源二聚化并抑制其激酶活性。此外，PRMT1的药理学抑制或基因敲除通过促进RIPK1介导的坏死性凋亡和凋亡加重I/R损伤，而PRMT1过表达则通过抑制RIPK1激活对I/R损伤起到保护作用。我们的研究结果揭示了RIPK1激活的分子调节机制，并表明PRMT1可能是治疗缺血性中风的潜在治疗靶点。
