A novel GPR84 antagonist attenuates diabetic lung injury by inhibiting pyroptosis via the cGAS-STING pathway in pulmonary vascular endothelial cells.

Diabetic lung injury (DLI) is a severe complication of diabetes, characterized by pulmonary vascular endothelial cell damage, inflammation, and pyroptosis. However, the underlying molecular mechanisms remain unclear. This study investigates the role of G-protein-coupled receptor 84 (GPR84) in DLI and its regulation of pyroptosis via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. We first established a DLI rat model and found that GPR84 expression was significantly upregulated in lung tissue. RNA sequencing and bioinformatics analysis identified a strong correlation between GPR84 and cGAS-STING pathway-related genes, including TBK1, CGAS, IFNA2, and STING1. Molecular docking analysis revealed that β-sitosterol, a natural compound from Sophora japonica, exhibited strong binding affinity to GPR84. In vitro experiments demonstrated that β-sitosterol effectively inhibited the cGAS-STING pathway, reducing pyroptosis and inflammatory cytokine secretion in pulmonary vascular endothelial cells. Furthermore, in vivo studies confirmed that β-sitosterol administration significantly attenuated lung inflammation, suppressed cGAS-STING activation, and reduced pyroptosis in diabetic rats. These findings highlight β-sitosterol as a novel GPR84 antagonist with therapeutic potential for mitigating DLI by inhibiting cGAS-STING-mediated pyroptosis. This study provides new insights into the pathogenesis of diabetic lung injury and potential molecular targets for therapeutic intervention.