银杏内酯A（GA）是从银杏中提取的主要萜类化合物，具有抗炎、抗肿瘤和保护肝脏等生物活性。但是，GA在治疗感染性心肌病方面的抑制作用仍不清楚。本研究旨在探讨GA对抵抗感染性心肌功能障碍和损伤的影响和机制。在脂多糖（LPS）诱导的小鼠模型中，GA减轻了线粒体损伤和心脏功能障碍。GA还显著减少了炎症和凋亡细胞的产生、炎性指标的释放，以及氧化应激相关和凋亡相关标志物的表达，但增加了LPS组心脏中关键抗氧化酶的表达。这些结果与基于H9C2细胞的体外实验结果一致。数据库分析和分子对接表明，FoxO1是GA的靶标，而GA与FoxO1的SER-39和ASN-29之间形成了稳定的氢键。GA逆转了H9C2细胞核中FoxO1表达的下调和p-FoxO1表达的上调。FoxO1敲除抵消了GA的保护性质。作为FoxO1下游基因的KLF15、TXN2、NOTCH1和XBP1也具有保护作用。我们得出结论，GA可以通过结合FoxO1来减轻LPS诱导的感染性心肌病，从而减轻心肌细胞炎症、氧化应激和凋亡。©2023 John Wiley＆Sons Ltd.

Ginkgolide A (GA), a main terpenoid extracted from Ginkgo biloba, possesses biological activities such as anti-inflammatory, anti-tumor, and liver protection. However, the inhibitory effects of GA on septic cardiomyopathy remain unclear. This study aimed to explore the effects and mechanisms of GA in countering sepsis-induced cardiac dysfunction and injury. In lipopolysaccharide (LPS)-induced mouse model, GA alleviated mitochondrial injury and cardiac dysfunction. GA also significantly reduced the production of inflammatory and apoptotic cells, the release of inflammatory indicators, and the expression of oxidative stress-associated and apoptosis-associated markers, but increased the expression of pivotal antioxidant enzymes in hearts from LPS group. These results were consistent with those of in vitro experiments based on H9C2 cells. Database analysis and molecular docking suggested that FoxO1 was targeted by GA, as shown by stable hydrogen bonds formed between GA with SER-39 and ASN-29 of FoxO1. GA reversed LPS-induced downregulation of nucleus FoxO1 and upregulation of p-FoxO1 in H9C2 cells. FoxO1 knockdown abolished the protective properties of GA in vitro. KLF15, TXN2, NOTCH1, and XBP1, as the downstream genes of FoxO1, also exerted protective effects. We concluded that GA could alleviate LPS-induced septic cardiomyopathy via binding to FoxO1 to attenuate cardiomyocyte inflammation, oxidative stress, and apoptosis.© 2023 John Wiley & Sons Ltd.