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Background: Luteolin is an active ingredient in various traditional Chinese medicines for the treatment of multiple tumors. However, the mechanisms of its inhibitory effect on osteosarcoma proliferation and metastasis remain unclear. Purpose: To elucidate the anti-osteosarcoma mechanisms of luteolin based on network pharmacology and experimental verification. Study Design: Integrate network pharmacology predictions, scRNA-seq analysis, molecular docking, and experimental validation. Methods: Luteolin-related targets and osteosarcoma-associated targets were collected from several public databases. The luteolin against osteosarcoma targets were screened and a PPI network was constructed to identify the hub targets. The GO and KEGG enrichment of osteosarcoma-associated targets and luteolin against osteosarcoma targets were performed. And scRNA-seq analysis was performed to determine the distribution of the core target expression in OS tissues. Molecular docking, cell biological assays, and osteosarcoma orthotopic mouse model was performed to validate the inhibitory effect and mechanisms of luteolin on osteosarcoma proliferation and metastasis. Results: Network pharmacology showed that 251 luteolin against osteosarcoma targets and 8 hub targets including AKT1, ALB, CASP3, IL6, JUN, STAT3, TNF, and VEGFA, and the PI3K-AKT signaling pathway might play an important role in anti-osteosarcoma of luteolin. Analysis of public data revealed that AKT1, IL6, JUN, STAT3, TNF, and VEGFA expression in OS tissue was significantly higher than that in normal bones, and the diagnostic value of VEGFA for overall survival and metastasis was increased over time. scRNA-seq analysis revealed significantly higher expression of AKT1, STAT3, and VEGFA in MYC+ osteoblastic OS cells, especially in primary samples. Moreover, the docking activity between luteolin and the hub targets was excellent, as verified by molecular docking. Experimental results showed that luteolin could inhibit cell viability and significantly decrease the expression of AKT1, STAT3, IL6, TNF, and VEGFA, and luteolin could also inhibit osteosarcoma proliferation and metastasis in osteosarcoma orthotopic mouse model. Conclusion: This study shows that luteolin may regulate multiple signaling pathways by targeting various genes like AKT1, STAT3, IL6, TNF, and VEGFA to inhibit osteosarcoma proliferation and metastasis. [ABSTRACT FROM AUTHOR]