Matrine Suppresses Osteosarcoma Lung Metastasis by Targeting the PI3K/AKT Signaling Pathway to Induce Mitochondrial Dysfunction

Objective: Osteosarcoma, the most common primary bone malignancy in children and adolescents, frequently metastasizes to the lung, with a five-year survival rate of about 20% after lung metastasis. This study assessed whether matrine suppresses osteosarcoma lung metastasis by inducing mitochondrial dysfunction through inhibition of the PI3K/AKT pathway. Methods: Using 143B, U2OS, and MG63 cells, we assessed proliferation, colony formation, and invasion; examined mitochondrial ultrastructure, membrane potential, and reactive oxygen species (ROS); and measured PI3K/AKT phosphorylation and mitochondrial dynamics and apoptosis-related proteins by Western blotting. Direct binding of matrine to PI3K was verified by molecular docking and surface plasmon resonance (SPR). Rescue experiments used the PI3K agonist 740 Y-P, and efficacy was tested in subcutaneous xenograft and tail vein lung metastasis models. Results: Matrine inhibited the proliferation, colony formation, and invasion of 143B, U2OS, and MG63 cells in a concentration-dependent manner, with 143B cells being the most sensitive, and in vivo, it suppressed tumor growth and lung metastasis without obvious organ toxicity. Mechanistically, matrine caused mitochondrial swelling, cristae rupture, membrane potential loss, and ROS accumulation; upregulated FIS1, Bax, and cytochrome c; and downregulated Mfn1 and Mfn2. It directly bound to PI3K and inhibited PI3K/AKT phosphorylation. The PI3K agonist 740 Y-P only partially reversed these effects, indicating partial dependence on the PI3K/AKT pathway. Conclusions: Matrine suppresses osteosarcoma lung metastasis by targeting the PI3K/AKT pathway to induce mitochondrial dysfunction and may be a useful therapeutic agent.