Multi-Omics Profiling of oxylipins and gene expression in pediatric sarcomas identifies metastatic signatures and prognostic models.

INTRODUCTION

Pediatric bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive malignancies with poor prognosis in the metastatic stage. Oxylipins, bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs), play a crucial role in inflammation, immunity, and cancer progression; however, their systemic profiles in pediatric sarcomas remain unexplored.

METHODS

We performed UPLC-MS/MS-based metabolomic profiling of plasma oxylipins and PUFAs in 52 pediatric sarcoma patients (29 OS, 23 ES) and 20 healthy controls. Transcriptomic data from public datasets (GSE99671, TARGET-OS) were integrated to identify oxylipin-related dysregulated genes in osteosarcoma and to construct a prognostic model.

RESULTS

Sarcoma patients exhibited distinct oxylipin profiles, with significant elevations in linoleic acid metabolites (9-HODE, 9-HpODE, 13-KODE), particularly in stage IV metastatic disease. Transcriptomic analysis revealed dysregulation of oxylipin metabolism genes, including PLA2G4B, CYP2C8, CYP4A22, CYP2S1, and cannabinoid metabolism genes FAAH and CNR1. Based on the analysis of 202 oxylipin metabolism-related genes, a 21-gene prognostic signature was derived, which effectively stratified osteosarcoma patients into high- and low-risk groups with significant survival differences. The model demonstrated high prognostic accuracy (AUC values of 0.910, 0.900, and 0.919 for 1-, 3-, and 5-year overall survival, respectively) and was validated in an independent cohort (GSE21257).

CONCLUSIONS

This first comprehensive oxylipin metabolomics study in pediatric bone sarcomas identifies plasma lipid mediators as potential biomarkers for metastasis and prognosis. The integration of metabolomic and transcriptomic data highlights oxylipin pathway dysregulation as a key feature of sarcoma biology, offering new opportunities for risk stratification and targeted therapy.