Acute lung injury (ALI) is a life-threatening clinical disorder with high mortality rate. Ferroptosis is a new type of programmed cell death with lipid peroxidation and iron ion overloading as the main characteristics. Endoplasmic reticulum (ER) stress and ferroptosis play pivotal roles in the pathogenesis of ALI. The study aimed to investigate the underlying relationship between ER stress and ferroptosis in ALI. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated LPS-induced inflammation, and decreased IL-1β, IL-6, and TNF-α levels in BALF and lungs. The increased MDA and decreased GSH induced by LPS were partially reversed by 4-PBA, which also inhibited the expressions of ferroptosis-related protein ACSL4, COX-2, and FTH1. TEM further confirmed the ferroptosis within airway epithelia cells was ameliorated by 4-PBA. Moreover, 4-PBA reduced the production of ROS and lipid ROS in LPS-exposed BEAS-2B cells in a concentration-dependent way. Meanwhile, 4-PBA mitigated LPS-induced cell apoptosis in vivo and in vitro. Mechanistically, the MAPK signaling pathway activated by LPS was downregulated by 4-PBA. Collectively, these findings suggested that 4-PBA protected against ALI by inhibiting inflammation and ferroptosis through downregulating ER stress, thus providing a potential intervention for ALI and revealing the possible interaction between ER stress and ferroptosis in ALI.

急性肺损伤（ALI）是一种危及生命的临床疾病，死亡率很高。铁死亡是一种以脂质过氧化和铁离子超载为主要特征的新型程序性细胞死亡。内质网 (ER) 应激和铁死亡在 ALI 的发病机制中发挥着关键作用。该研究旨在探讨 ALI 中 ER 应激与铁死亡之间的潜在关系。 ER 应激抑制剂 4-苯基丁酸 (4-PBA) 可减轻 LPS 诱导的炎症，并降低 BALF 和肺部中 IL-1β、IL-6 和 TNF-α 的水平。 LPS 诱导的 MDA 增加和 GSH 减少被 4-PBA 部分逆转，4-PBA 还抑制铁死亡相关蛋白 ACSL4、COX-2 和 FTH1 的表达。 TEM 进一步证实 4-PBA 可以改善气道上皮细胞内的铁死亡。此外，4-PBA 以浓度依赖性方式减少 LPS 暴露的 BEAS-2B 细胞中 ROS 和脂质 ROS 的产生。同时，4-PBA在体内和体外减轻LPS诱导的细胞凋亡。从机制上讲，LPS 激活的 MAPK 信号通路被 4-PBA 下调。总的来说，这些发现表明，4-PBA 通过下调 ER 应激来抑制炎症和铁死亡，从而预防 ALI，从而为 ALI 提供潜在的干预措施，并揭示 ALI 中 ER 应激和铁死亡之间可能存在的相互作用。