The contribution of the novel CLTC-VMP1 fusion gene to autophagy regulation and energy metabolism in cisplatin-resistant osteosarcoma

Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance is a major challenge in the treatment of this disease. This study aims to explore the role of the CLTC-VMP1 gene fusion in the mechanism of chemotherapy resistance in OS and investigate its molecular mechanisms in mediating energy metabolism reprogramming by regulating autophagy and apoptosis balance. Using single-cell transcriptome analysis, the heterogeneity of OS cells and their correlation with resistance to platinum drugs were revealed. Cisplatin-resistant cell lines were established in human OS cell lines for subsequent experiments. Based on transcriptomic analysis, the importance of VMP1 in chemotherapy resistance was confirmed. Lentiviral vectors overexpressing or interfering with VMP1 were used, and it was observed that inhibiting VMP1 could reverse cisplatin resistance, promote cell apoptosis, and inhibit autophagy, and mitochondrial respiration and glycolysis. Furthermore, the presence of CLTC-VMP1 gene fusion was validated, and its ability to regulate autophagy and apoptosis balance, promote mitochondrial respiration, and glycolysis was demonstrated. Mouse model experiments further confirmed the promoting effect of CLTC-VMP1 on tumor growth and chemotherapy resistance. In summary, the CLTC-VMP1 gene fusion mediates energy metabolism reprogramming by regulating autophagy and apoptosis balance, which promotes chemotherapy resistance in OS.<b>NEW & NOTEWORTHY</b> This study identifies the CLTC-VMP1 gene fusion as a key driver of chemotherapy resistance in osteosarcoma by regulating autophagy and reprogramming cellular energy metabolism. Through single-cell transcriptomics, the research reveals the heterogeneity of tumor cells and the role of VMP1 in promoting resistance to cisplatin. The findings suggest that targeting the CLTC-VMP1 fusion gene may offer new therapeutic strategies to overcome chemotherapy resistance in osteosarcoma.