Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.

炎症引起的神经变性是多发性硬化症（MS）的一个明确特征，但其潜在机制仍不清楚。通过剖析神经元炎症应激反应，我们发现多发性硬化症及其小鼠模型中的神经元会诱导干扰素基因刺激物（STING）。然而，神经元 STING 的激活需要其与基质相互作用分子 1 (STIM1) 分离，这是由谷氨酸兴奋毒性触发的过程。这种脱离启动了非经典的 STING 信号传导，导致谷胱甘肽过氧化物酶 4 (GPX4) 的自噬降解，而谷胱甘肽过氧化物酶 4 (GPX4) 对于神经元氧化还原稳态至关重要，从而诱导铁死亡。针对神经元中的 STING 的遗传和药理学干预措施可防止炎症引起的神经变性。我们的研究结果将 STING 定位为有害神经元炎症应激反应的中心调节因子，将炎症与谷氨酸信号传导相结合，导致神经元细胞死亡，并将其作为治疗多发性硬化症神经变性的易处理靶点。