Abstract: OBJECTIVE To explore the therapeutic effect and mechanism of sinensetin on diabetic kidney disease. METHODS In vitro cell injury model was constructed by incubating human renal glomerular microvascular endothelial cells (HRGEC) using the reducing body Trx1 exogenous inhibitor of Px-12. Control group, Px-12 group, sinensetin group, sinensetin+Px-12 group, N-acetyl-L-cysteine(NAC) group, NAC+Px-12 group, PD98059 group and PD98059+Px-12 group were established. Cells were pretreated with sinensetin, the oxidative stress inhibitor NAC, and the extracellular regulatory protein kinase(ERK1/2) inhibitor PD98059, and then co-incubated with Px-12. Cell morphology was observed, and CCK-8 was used to determine cell viability. The among-group difference level of oxidative stress of HRGEC in each group was determined by using reactive oxygen species(ROS)/O₂^- fluorescence probe. The changes in membrane morphology in each group were observed by transmission electron microscopy, and the protein expression of gasdermin D(GSDMD), ERK1/2 phosphorylation, and gap junction protein 43(Connexin 43, Cx43) proteins were detected by Western blotting. RESULTS Px-12 could induce the breakdown of HRGEC membrane integrity and expose the NT terminal of GSDMD, leading to pyroptosis(P<0.01). Px-12 could significantly induce the upregulation of ROS/O₂^- and activate the oxidative stress level(P<0.01). On the contrary, sinensetin could markedly inhibit Px-12-induced increase of ROS/O₂^-(P<0.05) and reduce Px-12-induced formation of GSDMD-NT and ERK phosphorylation(P<0.01 or P<0.05). Px-12 could induce an enhancement of Cx43 expression(P<0.01), while the inhibitor of ERK signaling inhibitor could significantly inhibit Cx43 expression(P<0.01). Coincidently, sinensetin had the similar function (P<0.01). CONCLUSION Sinensetin can alleviate Px-12-induced HRGEC pyroptosis, which is probably related to the regulation of the ERK-MAPK-Cx43 signaling pathway.