The Protective Effects of Vanillic Acid on LPS-induced Acute Lung Injury by Inhibiting STIM1-mediated NLRP3...

Acute lung injury (ALI), which can progress to acute respiratory distress syndrome (ARDS), has inflammation as a crucial factor, especially the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome involvement. Stromal interaction molecule 1 (STIM1) can block NLRP3 activation, but the mechanism is unclear. Vanillic acid, possessing anti-inflammatory properties, has a role in acute lung injury (ALI) whose specific mechanism remains unclear. This study aimed to investigate the effectiveness of vanillic acid in ALI induced by lipopolysaccharides (LPS) and to elucidate the potential mechanisms. In vitro and in vivo experiments were conducted using cells and a mouse model to find out the impact and underlying mechanisms. We found that vanillic acid demonstrated significant inhibition of IL-1β and IL-18 release triggered by LPS and nigericin in J774A.1 cells. The in vivo findings indicated that vanillic acid not only mitigated acute lung injury but also suppressed NLRP3 inflammasome activation in mice. Mechanistically, vanillic acid inhibited the LPS-induced increase in STIM1 expression through the lysosomal degradation pathway. The reduced STIM1 expression diminished intracellular Ca²⁺ levels, thereby suppressing inflammasome activation and impeding the cleavage and maturation of Caspase-1 and GSDMD, and eventually attenuating cell pyroptosis. Vanillic acid exerts its inhibitory effects on NLRP3 inflammasome activation by promoting STIM1 degradation, thereby ameliorates ALI through impeding NLRP3-GSDMD mediated pyroptosis. The STIM1-NLRP3 signaling axis represents a promising avenue for potential therapeutic interventions in ALI.