• Hernandezine suppresses lipopolysaccharide-induced macrophage pro-inflammatory polarization by downregulating Toll-like receptor 4/nuclear factor κB signaling in a concentration-dependent manner.
• Hernandezine inhibits osteoclast differentiation and bone resorption-related gene expression in vitro, also in a concentration-dependent manner.
• In an ovariectomized mouse model, Hernandezine treatment reduces bone loss, with the 10 mg/kg dose showing superior recovery.
• Hernandezine represents a potential therapeutic agent for osteoporosis by modulating macrophage polarization and osteoclast activation.