Abstract

Background Osteosarcoma, the leading type of primary bone cancer in adolescents, has a dismal prognosis in metastatic or relapsed patients, highlighting the urgent need for innovative treatments. Pomolic acid (PA), a naturally occurring pentacyclic triterpenoid, exhibits anticancer potential, but its activity and mechanisms in osteosarcoma remain poorly defined. Purpose This study focused on the antitumor effects of PA on osteosarcoma and elucidated the underlying molecular pathways, with additional performed in vivo . Methods Human osteosarcoma cell lines (143B and MG63) were used to examine the influence of PA on cell growth, apoptosis, cell cycle distribution, motility, invasion, and autophagy. Transcriptomic profiling was performed using RNA sequencing. An MG63 subcutaneous xenograft model was further utilized to assess therapeutic efficacy and safety in vivo . Results PA markedly inhibited osteosarcoma cell viability in a dose- and time- dependent manner, triggered G2/M phase arrest, and induced apoptosis. It also substantially reduced migration and invasion, likely through the reversal of epithelial mesenchymal transition (EMT). Transcriptomic data indicated that TNF/NF-κB signaling and autophagy pathways were modulated. In the xenograft model, PA treatment significantly suppressed tumor progression without evident toxicity. Conclusion PA demonstrated robust anti-osteosarcoma activity in vitro and in vivo . Its mechanisms include blocking proliferation, inducing apoptosis and cell cycle arrest, attenuating metastatic behaviors linked to EMT, and modulating autophagy, possibly through interference with the TNF/NF-κB signaling axis. These findings suggest that PA is a promising candidate for osteosarcoma therapy, warranting further preclinical and clinical evaluation.