Myricetin Inhibits Osteosarcoma Cell Viability and Modulates EMT-Related Genes Associated with the SNAI1/MMP-9 Axis

Background/Objectives: Osteosarcoma treatment options remain limited due to tumor metastasis and the toxicity of conventional chemotherapy, warranting new therapeutic strategies. A well-founded strategy is the use of flavonoids, a class of phytochemicals possessing pharmaceutical properties that contribute to anticancer effects, including antioxidant and anti-inflammatory properties. This study aimed to evaluate the anticancer potential of flavonoids in osteosarcoma and investigate their interaction with doxorubicin. Methods: In this study, five flavonoids were screened for cytotoxicity and selectivity across four osteosarcoma cell lines and healthy fibroblasts (MRC-5). The interaction between myricetin and doxorubicin was assessed using a fixed-ratio combination approach. Cell migration and invasion were evaluated using cell exclusion/wound healing and 2D co-culture assays. EMT-related gene expressions were assessed by RT-qPCR. Antitumor activity was evaluated in vivo using a chick chorioallantoic membrane (CAM) xenograft model. Results: Myricetin emerged as the most selective compound, exhibiting cytotoxicity against osteosarcoma cells while sparing MRC-5 fibroblasts. Notably, myricetin synergized with doxorubicin (ratio 69:1), enhancing its cytotoxicity and significantly reducing osteosarcoma cell migration in vitro. Myricetin downregulated SNAI1 and MMP9, suggesting modulation of epithelial–mesenchymal transition (EMT)-related pathways. Complementarily, in the CAM xenograft model, myricetin reduced xenograft tumor size, confirming its anticancer activity in vivo. Conclusions: Collectively, these findings emphasize the anticancer potential of myricetin in osteosarcoma through inhibition of the SNAI1/MMP-9 signaling axis.