Accumulated evidence implicates lipid peroxidation as a key mechanism contributing to the pathogenesis of lupus nephritis (LN). Ferroptosis is a specialized form of cell death induced by loss or deficient activity of the glutathione peroxidase 4 (GPX4) and decreased clearance of polyunsaturated fatty acid hydroperoxides. STING production may lead to the occurrence of intracellular lipid peroxidation, ultimately triggering ferroptosis, but it has not been clarified whether STING can aggravate LN via ferroptosis. The adjacent normal kidney tissues from renal cell carcinoma and biopsied kidney tissue samples from LN patients were used for research, and the expression of STING protein in kidney tissue was detected by immunohistochemistry and RT-qPCR. MRL/lpr mice, a model of LN, were used to detect STING expression in kidney tissue. STING expression in the kidney tissue of MRL/lpr mice was knocked down by sh-STING-AAV, and then levels of 4-HNE, MDA, ROS, iron ion, blood urea nitrogen and serum creatinine, IL-6, IL-1β, and TNF-α, and the protein expression of STING, TBK1, NF-κB, GPX4, ACSL4, and SLC7A11 were subsequently examined. STING was elevated in the kidney tissue of LN patients and MRL/lpr mice. Compared with the MRL/lpr group, liproxstatin-1 or ferrostatin-1 treatment alleviated ferroptosis-related indicators 4-HNE, MDA, ROS, iron ion release, and GPX4 and SLC7A1 expression, whereas the treatment enhanced ACSL4 expression. STING interference observably decreased 4-HNE, ROS, MDA, iron ion, STING, and ACSL4 levels, and increased GPX4 and SLC7A11 expression in MRL/lpr mice kidney tissues. Besides, inhibition of STING reduced kidney tissue damage and inflammatory cell infiltration in MRL/lpr mice, and levels of serum creatinine, blood urea nitrogen, serum anti-double-stranded DNA antibody, inflammatory factors IL-6, IL-1β, and TNF-α, as well as phosphorylation of NF-κB were all significantly decreased in MRL/lpr mice. TBK1 overexpression reversed the impact of STING inhibition on ferroptosis and inflammatory response. STING contributed to ferroptosis and inflammatory response by activating the TBK1/NF-κB pathway, suggesting that STING may be a potent therapeutic target in LN.

积累的证据表明脂质过氧化是狼疮性肾炎 (LN) 发病机制的关键机制。铁死亡是一种特殊形式的细胞死亡，由谷胱甘肽过氧化物酶 4 (GPX4) 活性丧失或不足以及多不饱和脂肪酸氢过氧化物清除率降低引起。STING的产生可能导致细胞内脂质过氧化的发生，最终引发铁死亡，但目前尚不清楚STING是否可以通过铁死亡加重LN。采用肾细胞癌的癌旁正常肾组织和LN患者的活检肾组织样本进行研究，通过免疫组化和RT-qPCR检测肾组织中STING蛋白的表达。MRL/lpr小鼠（LN模型）用于检测肾组织中STING的表达。sh-STING-AAV敲低MRL/lpr小鼠肾组织中STING的表达，进而降低4-HNE、MDA、ROS、铁离子、血尿素氮和血清肌酐、IL-6、IL-1β的水平随后检查了STING、 TBK1 、NF-κB、GPX4、ACSL4 和 SLC7A11的蛋白表达。LN 患者和 MRL/lpr 小鼠的肾组织中 STING 升高。与MRL/lpr组相比，liproxstatin-1或ferrostatin-1治疗减轻了铁死亡相关指标4-HNE、MDA、ROS、铁离子释放以及GPX4和SLC7A1的表达，而治疗增强了ACSL4的表达。STING 干扰可显着降低 MRL/lpr 小鼠肾组织中的 4-HNE、ROS、MDA、铁离子、STING 和 ACSL4 水平，并增加 GPX4 和 SLC7A11 表达。此外，抑制STING可减少MRL/lpr小鼠的肾组织损伤和炎症细胞浸润，以及血清肌酐、血尿素氮、血清抗双链DNA抗体、炎症因子IL-6、IL-1β和TNF的水平MRL/lpr 小鼠中 -α 以及 NF-κB 磷酸化均显着降低。TBK1过表达逆转了 STING 抑制对铁死亡和炎症反应的影响。STING 通过激活TBK1 /NF-κB 通路导致铁死亡和炎症反应，表明 STING 可能是 LN 的有效治疗靶点。