Abstract：
Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.
摘要：
新的证据已经报道，急性肺损伤(ALI)，以气道上皮的炎症和氧化应激为特征，受程序性细胞死亡调节。Ferroptosis,由不受控制的脂质过氧化刺激的细胞死亡的调节形式，已被证明与各种疾病有关.通过抑制脂质过氧化，抑制铁凋亡是ALI的可行策略，而机制仍有待进一步阐明。这里,我们确定了在ALI期间，Sequestosome1（SQSTM1）是气道上皮铁性凋亡的负调节因子。SQSTM1敲低细胞对铁凋亡表现出更高的敏感性。机械上,发现SQSTM1通过其核受体（NR）盒基序与维生素D受体（VDR）直接相互作用，促进其核易位并在转录水平上启动自噬。为了进一步验证这些发现，利用亚精胺的体内预防模型，建立了一个成熟的SQSTM1诱导物。结果一致表明，补充亚精胺可显着诱导SQSTM1并通过减轻气道上皮铁凋亡来改善ALI。值得注意的是,这些效应在没有SQSTM1的情况下被消除.一起来看,这项研究确定SQSTM1是VDR介导的自噬方式的气道上皮铁凋亡的负调节因子，使其成为ALI治疗的潜在治疗靶点。
