Pelargonidin-3-<i>O</i>-galactoside Alleviates Acute Lung Injury Induced by <i>Klebsiella pneumoniae</i> by Targeting CD38-Mediated Pyroptosis

Antibiotic resistance has amplified the threat of bacterial-induced acute lung injury (ALI) to human health. In the quest for novel therapeutic strategies, natural products have shown promise in mitigating the severity of this condition. In this study, we explored the protective effects of pelargonidin-3-<i>O</i>-galactoside (Pg3gal) on <i>Klebsiella pneumoniae</i> (KP)-induced ALI and its underlying mechanisms. Our findings indicated that Pg3gal mitigated lung histopathological changes and edema by inhibiting the migration and infiltration of immune cells and by reducing the secretion of pro-inflammatory cytokines. Molecular docking and surface plasmon resonance analyses revealed that Pg3gal bound to CD38 with high affinity. Further investigation showed that Pg3gal downregulated CD38 expression by promoting its ubiquitination. The reduction of CD38 elevated NAD⁺ levels and SIRT1 expression and inhibited NF-κB p65 acetylation, thereby suppressing NLRP3 inflammasome-mediated pyroptosis. Our research demonstrates that Pg3gal exerts protective effects against KP-induced ALI by inhibiting pyroptosis through the CD38/SIRT1/NF-κB/NLRP3 signaling pathway, highlighting its potential as a therapeutic agent for ALI.