Recent studies have shown glycerolipid metabolism played an essential role in multiple tumors, however, its function in osteosarcoma is unclear. This study aimed to explore the role of glycerolipid metabolism in osteosarcoma.

We conducted bioinformatics analysis using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database and single-cell RNA sequencing. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify the Glycerolipid metabolism-related genes associated with the clinical outcome of osteosarcoma. Tumor-associated macrophages (TAMs) and their interactions with immune cells were examined through single-cell analysis and co-culture experiments. Virtual screening was employed to identify the potential lysophosphatidic acid receptor 6 (LPAR6) inhibitors.

Glycerolipid metabolism-related genes 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) and aldehyde dehydrogenase 7 family member A1 (ALDH7A1) were identified as key prognostic genes in osteosarcoma, with high AGPAT3 expression correlating with improved survival. Single-cell analysis revealed that AGPAT3 expression is associated with tumor immune microenvironment, particularly with TAMs. Knockdown of AGPAT3 in osteosarcoma cells resulted in elevated lysophosphatidic acid (LPA) levels, which regulated the immune environment, inhibiting cytotoxic T cell function through TAMs’ LPAR6 signaling. LPAR6 signaling in TAMs mediates immune regulation through cytokine secretion, including interleukin-6 (IL-6) and interleukin-10 (IL-10). Further drug virtual screening identified Dutasteride as a potential inhibitor of LPAR6.

AGPAT3 is an important gene related to the prognosis of osteosarcoma. Its ability to modulate LPA signaling and TAM activity offers promising therapeutic opportunities for improving osteosarcoma treatment, particularly in immunotherapy contexts.