• Network pharmacology identified 137 intersection targets of luteolin, macrophage polarization, and knee osteoarthritis, with NF-κB complex enriched in the protein-protein interaction network.
• Luteolin inhibits M1 polarization and promotes M2 polarization of RAW264.7 macrophages, shifting the balance toward an anti-inflammatory phenotype.
• Mechanistically, luteolin suppresses NF-κB p65/p50 nuclear translocation, promotes IκB-α expression, and inhibits its phosphorylation, thereby modulating the NF-κB signaling pathway.
• These findings suggest that luteolin holds potential as a therapeutic agent for knee osteoarthritis by regulating macrophage polarization via the NF-κB pathway.