Protocatechuic aldehyde restrains NLRP3 inflammasome activation to alleviate inflammatory response in sepsis

Sepsis, a life-threatening organ dysfunction syndrome triggered by infection, is characterized by complex pathophysiology involving dysregulated inflammation, coagulation abnormalities, and mitochondrial dysfunction. Excessive activation of the NLRP3 inflammasome plays a pivotal role in sepsis progression. This study investigated the therapeutic effects and underlying mechanisms of protocatechuic aldehyde (PCA) in sepsis. Seventy-five potential PCA targets for sepsis were identified, with KEGG enrichment highlighting involvement in inflammatory and apoptotic pathways. PPI network analysis pinpointed TNF, IL-6, and IL-1β as key inflammatory targets. PCA dose-dependently suppressed IL-1β and TNF-α release in LPS/ATP-stimulated macrophages, reduced ASC speck formation and NLRP3-ASC interaction, and decreased mt-ROS production and TXNIP-NLRP3 co-localization. PCA also preserved mitochondrial network integrity by interacting with mitochondrial dynamics proteins DRP1 and MFN2, improving mitochondrial membrane potential and morphology. In LPS-induced septic mice, PCA significantly reduced serum IL-1β and TNF-α levels, improved survival rates, and downregulated NLRP3, pro-IL-1β, and cleaved-IL-1β expression in peritoneal macrophages. PCA alleviates inflammatory responses and organ damage in septic mice by inhibiting the mt-ROS/TXNIP/NLRP3 signaling axis and maintaining mitochondrial function, offering a promising natural therapeutic candidate for sepsis.