Luteolin reprograms macrophage polarization via the STING-TBK1 pathway to accelerate bone repair

Macrophages play a pivotal role in bone regeneration, making their polarization a key target for immune regulation and therapeutic intervention. Modulating macrophage polarization represents a promising strategy for enhancing bone repair. Luteolin, a plant-derived flavonoid with well-documented anti-inflammatory properties, has been explored for its role in bone repair. However, its specific effects on macrophage polarization in bone repair remain unclear. This study investigates the role of luteolin in macrophage polarization and its underlying mechanisms. Our findings demonstrate that luteolin promotes M2 polarization while suppressing M1 polarization, as indicated by a reduction in the expression of pro-inflammatory markers, including IL-6 and iNOS, and an increase in the expression of anti-inflammatory factors, such as CD206, IL-10, and TGF-β. Mechanistically, luteolin inhibits STING oligomerization, thereby suppressing the STING-TBK1 pathway and mitigating downstream inflammatory responses. <i>In vivo</i>, in a mouse tibial bone defect model, luteolin effectively alleviates inflammation, facilitates angiogenesis, enhances collagen deposition, and improves bone density. Collectively, these findings highlight the potential of luteolin as a therapeutic agent for bone repair by modulating macrophage polarization and inhibiting STING-TBK1 signaling.