Acute lung injury (ALI) is characterized with a high rate of morbidity and mortality. The injury and apoptosis of lung epithelial cells play crucial roles in the progression of ALI. Mixed lineage kinase 3 (MLK3) has been reported to be involved in the regulation of cellular biological functions, such as cell proliferation, apoptosis and ferroptosis. However, the effect of MLK3 exerted on ALI has not been reported. Here, LPS-stimulated MLE12 pulmonary epithelial cells were used as an in vitro model for ALI. In this research, LPS elevated the expression of MLK3 in MLE12 cells. The silence of MLK3 alleviated LPS-induced cell injury. Notably, LPS promoted ferroptosis through enhancing GSH depletion and the productions of MDA and iron, which was attenuated by MLK3 knockdown. Moreover, the silence of MLK3 inhibited p53 expression in LPS-induced cells along with a decrease in the expressions of p21 and Bax, while overexpressing p53 reversed these effects of MLK3 silence. Meanwhile, p53 overexpression reversed the positive effects of MLK3 knockdown on LPS-induced cell ferroptosis and injury. Together, our results confirmed that the silence of MLK3 alleviated LPS-induced lung epithelial cell injury by inhibiting p53-mediated ferroptosis.

急性肺损伤 (ALI) 的特点是发病率和死亡率很高。肺上皮细胞的损伤和凋亡在ALI的进展中起着至关重要的作用。据报道，混合谱系激酶 3 (MLK​​3) 参与调节细胞生物学功能，例如细胞增殖、凋亡和铁死亡。然而，尚未报道 MLK3 对 ALI 的影响。在这里，LPS 刺激的 MLE12 肺上皮细胞被用作体外ALI的模型。在这项研究中，LPS 提高了 MLE12 细胞中 MLK3 的表达。MLK3 的沉默减轻了 LPS 诱导的细胞损伤。值得注意的是，LPS 通过增强 GSH 消耗和 MDA 和铁的产生来促进铁死亡，而 MLK3 敲低则减弱了这种作用。此外，MLK3 的沉默抑制了 LPS 诱导的细胞中 p53 的表达，同时降低了 p21 和 Bax 的表达，而过表达 p53 则逆转了 MLK3 沉默的这些影响。同时，p53 过表达逆转了 MLK3 敲低对 LPS 诱导的细胞铁死亡和损伤的积极作用。总之，我们的结果证实，MLK3 的沉默通过抑制 p53 介导的铁死亡减轻了 LPS 诱导的肺上皮细胞损伤。