Molecular characterization of ferroptosis in soft tissue sarcoma constructs a prognostic and immunotherapeutic signature through experimental and bioinformatics analyses

Ferroptosis regulators have been found to affect tumor progression. However, studies focusing on ferroptosis and soft tissue sarcoma (STS) are rare. Somatic mutation, copy number variation, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, consensus clustering, differentially expressed genes analysis (DEGs), principal component analysis (PCA) and gene set enrichment analysis (GSEA) were used to identify and explore different ferroptosis modifications in STS. A nomogram was constructed to predict the prognosis of STS. Moreover, three immunotherapy datasets were used to assess the Fescore. Western blotting, siRNA transfection, EdU assay and reactive oxygen species (ROS) measurement were performed. 16 prognostic ferroptosis regulators were screened and significant differences were observed in somatic mutation, copy number variation (CNV) and RT-qPCR among these ferroptosis regulators. 2 different ferroptosis modification patterns were found (Fe cluster A and B). Fe cluster A with higher Fescore was correlated with p53 pathway and had better prognosis of STS (p = 0.002) while Fe cluster B with lower Fescore was correlated with angiogenesis and MYC pathway and showed a poorer outcome. Besides, the nomogram effectively predicted the outcome of STS and the Fescore could also well predict the prognosis of other 16 tumors and immunotherapy response. Downregulation of LOX also inhibited growth and increased ROS production in sarcoma cells. The molecular characterization of ferroptosis regulators in STS was explored and an Fescore was constructed. The Fescore quantified ferroptosis modification in STS patients and effectively predicted the prognosis of a variety of tumors, providing novel insights for precision medicine.