Exploring Mitochondrial Autophagy Dysregulation in Osteosarcoma: Its Implications for Prognosis and Targeted Therapy.

Objective: This study aimed to investigate the differential expression of mitophagyrelated genes in osteosarcoma patients with distinct prognostic outcomes and explore potential molecular regulatory mechanisms.

Methods: We analyzed microarray data from metastatic and nonmetastatic osteosarcoma patients using the UCSC dataset. Differential gene screening and intersection of mitophagy-related genes were performed using NetworkAnalyst. Random forest and LASSO regression were employed to screen selected genes and establish a risk prediction model. Functional enrichment analysis, protein- protein interaction (PPI) networks, immunoassays, and in vitro experiments were conducted to validate the findings.

Results: Seven differentially expressed genes were identified, and a robust risk prediction model was developed (AUC=0.886). PPI and functional enrichment analyses provided insights into relevant molecules and regulatory pathways. The immunoassay results revealed differences in the immune environment between the metastatic and nonmetastatic groups. Immunohistochemistry demonstrated significant downregulation of EPHA3 expression in the metastatic group, and in vitro experiments indicated that inhibiting EPHA3 increased the proliferative activity and migration ability of osteosarcoma cells.

Conclusion: Our study suggests that the downregulation of EPHA3 may contribute to mitochondrial autophagy dysfunction, thereby increasing the risk of osteosarcoma metastasis.