Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS–STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress–induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.

干扰素刺激基因（STING）对于感应细胞质DNA并启动针对微生物感染和肿瘤的先天免疫应答至关重要。氧化还原稳态是所有生命系统中存在的氧化反应和还原反应的平衡。然而，细胞内氧化还原状态如何控制STING激活尚不清楚。在这里，我们表明，由谷胱甘肽过氧化物酶4（GPX4）维持的细胞氧化还原稳态是STING激活所必需的。GPX4缺乏症会增强细胞脂质过氧化作用，因此特别抑制cGAS–STING途径。相应地，GPX4缺乏抑制单纯疱疹病毒1（HSV-1）诱导的先天抗病毒免疫反应并促进体内HSV-1复制。从机理上讲，GPX4失活增加了脂质过氧化的产生，导致C88处STING羰基化，并抑制其从内质网（ER）转运至高尔基体。因此，细胞应激诱导的脂质过氧化作用特别减弱了STING DNA的传感途径，表明GPX4通过维持脂质的氧化还原稳态来促进STING活化。