Piper aduncum L. has long been used in traditional medicine for its notable antimicrobial, anti-diarrheal, and anti-inflammatory properties. Flavonoids are recognized as the principal bioactive constituents of this plant, among which isoembigenin (IEGN) has been shown to inhibit dendritic cell-mediated inflammatory responses. However, its effects on other immune cell types involved in inflammation remain unclear. In this study, we examined whether IEGN pre-treatment could attenuate macrophage activation triggered by lipopolysaccharide (LPS). Our results demonstrated that IEGN significantly suppressed TNF-α expression in RAW 264.7 macrophages upon LPS stimulation. Moreover, in a murine sepsis model, IEGN pre-treatment markedly reduced the production of proinflammatory cytokines, including TNF-α and IL-1β, shortly after LPS challenge. Importantly, IEGN administration substantially improved the survival rate of BALB/c mice subjected to endotoxin-induced shock. Finally, the molecular docking simulation was a hypothetical assessment of the interaction between IEGN and iNOS and COX-2. Taken together, these findings highlight the therapeutic potential of IEGN as a candidate for preventing inflammation driven by macrophage activation.
