Ferroptosis plays a pivotal role in the pathological process of sepsis-induced cardiomyopathy (SIC). All-trans retinoic acid (ATRA) enhances the host immune response to lipopolysaccharides (LPS). This study investigated the role of 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a derivative of ATRA, in myocardial injury caused by sepsis. Male C57BL/6 mice were intraperitoneally injected with LPS to establish a sepsis model. H9c2 cells were stimulated by LPS to establish an injury model. We observed that ATPR improved myocardial injury in mice, which was presented in terms of an increased glutathione (GSH) level and reduced production of malondialdehyde (MDA), as well as an increased number of mitochondrial cristae and maintenance of the mitochondrial membrane integrity. ATPR improved cardiac function in the LPS-injured mice. It inhibited the inflammatory response as evidenced by the decreasing mRNA levels of TNF-α and IL-6. The elevated protein expression levels of Nrf2, SLC7A11, GPX4, and FTH1 in mice and H9c2 cells showed that ATPR inhibited ferroptosis. Immunoprecipitation of LPS-stimulated H9c2 cells demonstrated that ATPR increased the interaction between p62 and Keap1. ATPR upregulated the KLF4 and p62 protein expression. However, the inhibition of Nrf2 by ML385 reduced the protective effect of ATPR in LPS-treated H9c2 cells. Furthermore, we used siRNA to knock down KLF4 in H9c2 cells and found that the KLF4 knockdown eliminated the inhibition of ferroptosis by ATPR in H9c2 cells. Therefore, ATPR alleviates LPS-induced myocardial injury by inhibiting ferroptosis via the KLF4/p62 axis.

铁死亡在脓毒症诱发的心肌病（SIC）的病理过程中发挥着关键作用。全反式视黄酸 (ATRA) 增强宿主对脂多糖 (LPS) 的免疫反应。本研究调查了 ATRA 衍生物 4-氨基-2-三氟甲基-苯基视黄酸酯 (ATPR) 在脓毒症引起的心肌损伤中的作用。雄性C57BL/6小鼠腹腔注射LPS建立脓毒症模型。 LPS刺激H9c2细胞建立损伤模型。我们观察到 ATPR 改善了小鼠的心肌损伤，表现为谷胱甘肽 (GSH) 水平增加和丙二醛 (MDA) 产生减少，以及线粒体嵴数量增加和线粒体膜完整性的维持。 ATPR 改善了 LPS 损伤小鼠的心脏功能。它抑制了炎症反应，TNF-α 和 IL-6 mRNA 水平降低就证明了这一点。小鼠和 H9c2 细胞中 Nrf2、SLC7A11、GPX4 和 FTH1 蛋白表达水平升高表明 ATPR 抑制铁死亡。 LPS 刺激的 H9c2 细胞的免疫沉淀表明 ATPR 增加了 p62 和 Keap1 之间的相互作用。 ATPR 上调 KLF4 和 p62 蛋白表达。然而，ML385 对 Nrf2 的抑制降低了 ATPR 对 LPS 处理的 H9c2 细胞的保护作用。此外，我们使用siRNA敲低H9c2细胞中的KLF4，发现KLF4敲低消除了H9c2细胞中ATPR对铁死亡的抑制。因此，ATPR 通过 KLF4/p62 轴抑制铁死亡，从而减轻 LPS 诱导的心肌损伤。