Decursinol Protects Against Lipopolysaccharide-Induced Placental Inflammation and Trophoblast Dysfunction via Mitochondrial Preservation and NLRP3 Inflammasome Inhibition

Inflammation-induced placental dysfunction is a major contributor to pregnancy complications. Activation of NF-κB and NLRP3 inflammasome pathways in the placenta is a key driver of this pathology. Decursinol, a natural coumarin derivative from Angelica gigas, possesses anti-inflammatory properties; however, its effect on placental inflammation remains unclear. Therefore, in this study, we investigated the protective effects of decursinol against lipopolysaccharide (LPS)-induced placental inflammation and trophoblast dysfunction and explored the underlying molecular mechanisms. Decursinol significantly inhibited LPS-induced NLRP3 inflammasome activation and NF-κB/p65 signaling in Sw.71 human trophoblast cells, reducing interleukin-1β secretion and pro-inflammatory gene expression. It restored the trophoblast invasive capacity and preserved mesenchymal marker expression suppressed by LPS. It also improved the fetal and placental weights, restored the placental architecture, and attenuated placental NLRP3 inflammasome activation and cytokine expression in vivo. Mechanistically, decursinol preserved the mitochondrial homeostasis, reduced mitochondrial reactive oxygen species levels, and upregulated antioxidants and mitochondrial biogenesis-related gene levels, exerting effects comparable to those of mitochondria-targeted antioxidant Mito-TEMPO. These findings suggest that decursinol protects against LPS-induced trophoblast dysfunction and adverse pregnancy outcomes by preserving mitochondrial functions and suppressing NLRP3/NF-κB-mediated inflammation. Overall, our results highlight decursinol as a promising therapeutic candidate for inflammation-associated pregnancy complications.