Abstract

PurposeMyocardial ischemia-reperfusion (I/R) is characterized by myocardial cell death and exacerbated inflammatory responses that seriously affect cardiac function and patient prognosis. Limonin is a natural compound extracted from citrus fruits and has various biological activities, including anti-inflammatory and antioxidant activities. However, the role and mechanism of action of limonin in myocardial I/R injury remain unclear. This study aimed to explore the effects and underlying mechanisms of action of limonin on myocardial cell pyroptosis and inflammatory responses in mouse myocardial I/R injury.MethodsBy analyzing the GSE225105 dataset in the Gene Expression Omnibus database, differentially expressed genes in I/R injury were screened and combined with the target genes of limonin in the Comparative Toxicogenomics Database. In the in vitro experiments, The oxygen-glucose deprivation/reoxygenation (OGD/R) model was used to simulate I/R injury in in vitro experiments.ResultsLimonin significantly inhibited OGD/R-induced pyroptosis and the release of inflammatory factors in AC16 myocardial cells, and these effects could be reversed by the caspase-3/gasdermin E (GSDME) pathway activator triclabendazole. Using in vivo experiments, we established a myocardial I/R model in C57BL/6 mice and found that limonin pretreatment improved cardiac function-related indicators, reduced myocardial tissue damage and inflammatory responses, inhibited apoptosis, and reduced myocardial fibrosis. This mechanism is closely related to the inhibition of caspase-3/GSDME pathway activation.ConclusionThis study revealed the protective effects of limonin in reducing myocardial I/R injury by inhibiting the caspase-3/GSDME pathway, thereby providing a theoretical basis for the development of limonin-based myocardial protection strategies.