This study identifies neuronal STING as a central regulator of inflammation-induced neurodegeneration in multiple sclerosis (MS). Neuronal STING is activated by both interferon and glutamate-evoked intracellular calcium signaling, leading to autophagic degradation of glutathione peroxidase 4 (GPX4) and ferroptosis. The activation of neuronal STING requires its detachment from stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to the degradation of GPX4, essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions targeting neuronal STING protect against inflammation-induced neurodegeneration. These findings position STING as a key regulator of neuronal inflammatory stress response and present it as a potential therapeutic target for treating neurodegeneration in MS.This study identifies neuronal STING as a central regulator of inflammation-induced neurodegeneration in multiple sclerosis (MS). Neuronal STING is activated by both interferon and glutamate-evoked intracellular calcium signaling, leading to autophagic degradation of glutathione peroxidase 4 (GPX4) and ferroptosis. The activation of neuronal STING requires its detachment from stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to the degradation of GPX4, essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions targeting neuronal STING protect against inflammation-induced neurodegeneration. These findings position STING as a key regulator of neuronal inflammatory stress response and present it as a potential therapeutic target for treating neurodegeneration in MS.