Baimaside, a flavonoid glycoside from Apocynum venetum, ameliorates sepsis by allosterically inhibiting NF-κB p50-mediated IL-6 transcription.

Sepsis, a life-threatening inflammatory syndrome, is characterized by excessive cytokine production, particularly interleukin-6 (IL-6), which drives systemic inflammation and organ dysfunction. This study investigates the anti-inflammatory mechanism of Baimaside, a flavonoid compound isolated from Apocynum venetum, in lipopolysaccharide (LPS)-induced sepsis. Using bone marrow-derived macrophages (BMDMs) and a murine sepsis model, we demonstrate that Baimaside potently inhibits IL-6 transcription and secretion by disrupting the binding of NFκB1 p50 to the κB DNA element in the IL-6 promoter. Molecular docking and mutagenesis studies reveal that Baimaside binds p50 at residues Gly61, Ser63, Asn 136 etc., inducing steric hindrance that prevents p50 recruitment to the promoter. This inhibition selectively suppresses IL-6 expression while sparing other inflammatory mediators like TNF-α and IL-1β, which are regulated by classical NF-κB pathways. In vivo, Baimaside pretreatment significantly reduces LPS-induced organ injury, improves survival rates, and attenuates systemic inflammation in mice. These findings establish Baimaside as a novel therapeutic candidate for sepsis, acting through a unique mechanism targeting the p50-IL-6 axis. This study provides a mechanistic foundation for developing Baimaside into a precision medicine agent for IL-6-driven inflammatory disorders.