Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

神经元凋亡在蛛网膜下腔出血 (SAH) 后的早期脑损伤 (EBI) 中具有重要作用。TRAF3 被报道为中风管理的有希望的治疗靶点，它涵盖了几个神经元凋亡信号级联。因此，本研究旨在确定 TRAF3 的下调是否对 SAH 诱导的 EBI 具有神经保护作用。通过血管内穿孔建立小鼠体内SAH模型。同时，将用氧血红蛋白处理的小鼠原代培养的皮层神经元应用于体外模拟 SAH。我们的结果表明 TRAF3 蛋白表达增加并在体内和体外 SAH 模型的神经元中表达。TRAF3 siRNA 逆转了 SAH 小鼠的神经元丢失并改善了神经功能缺损，并减少了 SAH 原代神经元的细胞死亡。从机制上讲，我们发现 TRAF3 直接与 TAK1 结合并增强 TAK1 的磷酸化和激活，这进一步增强了 NF-κB 和 MAPKs 通路的激活以诱导神经元凋亡。重要的是，人脑组织中 SAH 后 TRAF3 表达升高，主要在神经元中表达。总之，我们的研究表明，TRAF3 是 SAH 诱导的 EBI 中 MAPK 和 NF-κB 通路的上游调节剂，通过其与 TAK1 的相互作用和激活。此外，TRAF3 可以作为 SAH 诱导的 EBI 的新治疗靶点。总之，我们的研究表明，TRAF3 是 SAH 诱导的 EBI 中 MAPK 和 NF-κB 通路的上游调节剂，通过其与 TAK1 的相互作用和激活。此外，TRAF3 可以作为 SAH 诱导的 EBI 的新治疗靶点。总之，我们的研究表明，TRAF3 是 SAH 诱导的 EBI 中 MAPK 和 NF-κB 通路的上游调节剂，通过其与 TAK1 的相互作用和激活。此外，TRAF3 可以作为 SAH 诱导的 EBI 的新治疗靶点。