Potential protective function and causal association of LEPR in osteosarcoma

The highly heterogeneous properties and dynamic immunogenic features of osteosarcoma (OS) lead to limited therapeutic efficacy. The oncogenetic mechanisms of OS await further explanation, and new insights into therapeutic targets for OS remain urgent. We used single-cell RNA-sequencing data to identify cell type-specific differentially expressed genes between normal human osteocytes and OS cells. Subsequently, we analyzed the differential expression of leptin receptor (LEPR) in OS cell lines through in vitro experiments. We assessed the prognostic potential of LEPR and immune cell infiltration status associated with differential LEPR expression in OS patients. By integrating protein quantitative trait loci and methylation quantitative trait loci datasets with OS genome-wide association studies summary statistics, we performed Mendelian randomization analysis to elucidate the causal effect of LEPR on OS risk and identify cytosine-phosphate-guanine sites that may influence LEPR expression and OS risk. We observed lower LEPR expression in OS cell clusters compared to normal osteocyte clusters. RT-qPCR results indicated that the LEPR gene showed consistent differential expression in OS cells. Survival analysis revealed that lower LEPR expression was associated with worse survival outcomes in OS patients. OS patients with high LEPR expression tended to exhibit more immune cell infiltration. Mendelian randomization analysis indicated that genetically-determined LEPR was inversely associated with OS risk. We identified 8 methylation cytosine-phosphate-guanine sites within the LEPR promoter region causally associated with both lower LEPR protein expression and higher OS risk. Our integrated multi-omics analyses supported a causal association between LEPR expression and OS risk, suggesting that LEPR may offer protective benefits for OS patients. The relationship between LEPR and OS risk highlights the potential of LEPR as an early prognostic biomarker and may provide new insights into the etiology of OS.