Targeting signaling cascades by bioactive phytocompounds in osteosarcoma: A novel therapeutic approach

Osteosarcoma is a highly aggressive primary malignant bone tumor characterized by early metastatic potential and limited therapeutic options for recurrent or metastatic disease. Although the introduction of multiagent chemotherapy has improved patient outcome, long-term survival remains suboptimal, highlighting the need for novel, mechanism-driven therapeutic strategies. Recent studies have shown promising antineoplastic effects of bioactive phytochemicals in osteosarcoma. While individual investigations have explored the efficacy of various phytochemicals in the treatment of osteosarcoma, a comprehensive evaluation of these agents has not been performed. The aim of this review is to systematically and critically evaluate the preclinical efficacy, multitargeted molecular mechanisms, and translational limitations of bioactive phytochemicals as potential therapeutic agents for osteosarcoma. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided approach was employed to analyze preclinical studies investigating the effects of major phytochemical classes, including phenolics, sulfur-containing compounds, terpenoids, and alkaloids, in osteosarcoma models. These phytochemicals consistently demonstrated antiproliferative, proapoptotic, and antimetastatic effects through modulation of key oncogenic pathways, including phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin, and the mitogen-activated protein kinase pathway, as well as regulation of mitochondrial apoptosis and epithelial-mesenchymal transition. Several compounds also showed tumor growth suppression in animal models. Overall, the findings support the therapeutic potential of multitargeted phytochemicals in osteosarcoma management. However, significant limitations, including variability in bioavailability, dosing, and experimental models, currently hinder clinical translation. Future studies should prioritize standardized formulations, pharmacokinetic optimization, and rigorous in vivo validation to clarify their role in osteosarcoma prevention and treatment.