Abstract
BACKGROUND: Fatty acid metabolism disruptions affect low-grade gliomas (LGGs), with glioma cells depending on fatty acids for survival. Targeting fatty acid oxidation through the acyl-coenzyme A synthetase long-chain (ACSL) family could alleviate glioma growth and improve prognosis management. However, the integration of ACSLs for analyzing their relationship with LGGs remains unexplored. METHODS: We collected RNA expression data of ACSLs for LGGs from TCGA, GTEx, CGGA, and GEO datasets and validated the prognostic significance of gene expression in 37 glioma samples. DNA methylation data from UCSC Xena and promoter methylation levels via MEXPRESS were analyzed. Functional enrichments of co-expressed ACSLs genes were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. Protein-protein interaction networks were established via GeneMANIA, and cBioPortal assessed somatic mutations and copy number variations of ACSLs in LGGs. TIMER and TISIDB databases investigated the correlation between ACSLs expression and immune infiltration and checkpoint genes. Hazard ratios (HR) with 95% confidence intervals (95% CI) were computed, and net reclassification index and integrated discrimination improvement were estimated to evaluate the predictive capability of the prognosis model. RESULTS: Independent prognostic factors for overall survival included age, gender, tumor grade, MGMT promoter status, ACSL1, ACSL3, ACSL5, and ACSL6 expression levels. High ACSL1 (HR = 2.352, 95%CI: 1.647-3.359, P = 9.00E-06), ACSL3 (HR = 2.367, 95%CI: 1.547-3.624, P = 2.92E-04) and ACSL5 (HR = 2.329, 95%CI: 1.611-3.367, P = 2.80E-05) expression correlated with poor prognosis, while increased ACSL6 (HR = 0.449, 95%CI: 0.290-0.696, P = 1.02E-03) expression related to better survival rates. Furthermore, these associations were also confirmed in the validation datasets and our external cohort. Negative correlation between ACSL1 and ACSL3 gene expression and methylation was found. Functional enrichment analyses highlighted the roles of ACSL1 and ACSL5 in glioma mechanisms and immune function, with significant associations between somatic CNVs and immune cell infiltration. CONCLUSIONS: ACSL1 and ACSL5 exhibit prognostic significance in gliomas and influence tumor immunity and immune cell migration, providing valuable insights into LGG prognosis and therapeutic targets.