Exploration of the antitumor effect and mechanism of gambogic acid on osteosarcoma through network pharmacology and experimental pharmacology study.

Osteosarcoma (OS) is a highly aggressive bone cancer in children and adolescents with extremely poor prognosis. Gambogic acid (GA) is a natural compound derived from the resin of Garcinia hanburyi trees and has been reported to possess multiple antitumor effects. However, the comprehensive mechanism of GA intervention in OS remains unclear. In this study, network pharmacology and experiment pharmacology were employed to elucidate the mechanism by which GA inhibited OS. Firstly, GA exhibited significant inhibitory effects on OS in vitro and in vivo. Then, the network pharmacological analysis and molecular docking predicted 9 targets involved in necroptosis and apoptosis induced by GA in OS. The qRT-PCR and western blotting verified that GA could increase the apoptosis-related mRNA and protein expression levels, such as cleaved caspase-3, cleaved PARP, indicating that GA could activate apoptosis. Furthermore, proteins related to necroptosis such as RIPK1, RIPK3, and p-RIPK3 were upregulated, while MLKL initially increased and then decreased, implying a dynamic regulation of necroptosis signaling. In summary, our results identified potential targets and pathways of GA to exert anti-osteosarcoma effect, suggesting that GA is a candidate drug for the treatment of osteosarcoma.