Endothelial cell pyroptosis is a key factor promoting plaque instability in atherosclerosis (AS). Serum/Glucocorticoid Regulated Kinase 1 (SGK1) is upregulated in AS, but its upstream regulatory mechanisms and role in pyroptosis remain unclear. This study aims to elucidate the mechanism of action of the GATA Binding Protein 3 (GATA3)/SGK1 axis in ox-LDL-induced endothelial cell pyroptosis. "AS and pyroptosis" related genes were screened using bioinformatics analysis. Transcription factor binding sites in the SGK1 promoter region were predicted using JASPAR. After establishing a pyroptosis model in ox-LDL-induced mouse aortic endothelial cells (MAECs), the effects of the GATA3/SGK1 regulatory axis on pyroptosis were detected using qRT-PCR, LDH release assays, and ELISA; the regulatory relationship was validated using the GATA3 inhibitor Pyrrothiogatain and SGK1 overexpression; and the mechanism of action of SGK1 was elucidated using a Caspase1 inhibitor (VX-765). Bioinformatics analysis identified 65 pyroptosis-related genes that were upregulated in AS, and this study focused on SGK1. The SGK1 promoter region contains 4 GATA3 binding sites. Ox-LDL significantly upregulated GATA3, SGK1, cleaved-Caspase-1, GSDMD-N and NLRP3 expression, while pyrrothiogatain reduced SGK1 expression and alleviated cellular damage and excessive inflammation. SGK1 overexpression reversed the protective effect of Pyrrothiogatain. Mechanistic studies showed that SGK1 overexpression exacerbated ox-LDL-induced pyroptosis, while VX-765 significantly reversed this effect. This study elucidates that GATA3 activated SGK1 transcription by directly binding to its promoter region, thereby promoting Caspase1/GSDMD-dependent endothelial cell pyroptosis.
