Syringaresinol alleviates IgG immune complex induced acute lung injury via activating PPARγ and suppressing pyroptosis

Acute lung injury (ALI) is a life-threatening condition characterized by severe lung inflammation and tissue damage. In this study, we investigate the potential therapeutic efficacy of (+)-Syringaresinol (SYG), a natural compound known for its antioxidant and anti-inflammatory properties, in alleviating ALI induced by IgG immune complexes (IgG-IC). Using MH-S cells as a model, we explore SYG's ability to target peroxisome proliferator-activated receptor gamma (PPARγ) and its anti-inflammatory properties. Our comprehensive investigation aims to elucidate the specific molecular mechanisms underlying SYG's effects against pyroptosis, as revealed through transcriptomic analysis. Validation in C57BL/6 mice provides in vivo support. Our findings indicate that SYG effectively mitigates IgG-IC-induced lung damage, as evidenced by a significant reduction in lung inflammation and tissue injury. SYG treatment notably decreases pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1β) in both lung tissue and cells. Molecular docking analysis reveals SYG's robust binding to PPARγ, leading to the inhibition of IgG-IC-induced inflammatory signaling pathways. Additionally, transcriptomic analysis unveils SYG's potential in suppressing macrophage pyroptosis, potentially through the downregulation of key inflammatory mediators (NLRP3, GSDMD, Caspase-1). In summary, our study presents compelling evidence supporting SYG as an effective therapeutic agent for ALI. SYG's activation of PPARγ contributes to the suppression of NF-κB and C/EBPs expression, thereby mitigating inflammation. Moreover, SYG demonstrates the ability to inhibit macrophage pyroptosis by targeting the NLRP3/GSDMD/caspase-1 axis.