Abstract
BACKGROUND: Pancreatic adenocarcinoma (PAAD) constitutes a lethal malignancy, notorious for its elevated mortality rates due to the difficulties in early diagnosis and rapid metastasis. The emerging paradigm of ferroptosis-an iron-catalyzed, regulated cell death distinguished by the accrual of lipid peroxides-has recently garnered scholarly focus. However, the expression landscape of ferroptosis-related genes (FRGs) in PAAD and their prognostic implications remain enigmatic. METHODS: We undertook a rigorous quantification of FRGs in PAAD samples, sourcing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. These repositories also provided extensive metadata, encompassing mesenchymal stemness index (mRNAsi), genomic mutations, copy number variations (CNV), tumor mutational burden (TMB), and other clinical attributes. A predictive model was constructed utilizing Lasso regression analysis, and a co-expression study was executed to elucidate the complex interconnections between FRGs and other gene sets. RESULTS: Intriguingly, FRGs were substantially upregulated in the high-risk cohort, even in the absence of clinically manifest symptoms, emphasizing their utility as prognostic biomarkers. Gene set enrichment analysis (GSEA) revealed significant enrichment of immune and tumor-related pathways in this high-risk demographic. Striking heterogeneities in immune function and N6-methyladenosine (m6A) RNA modification were observed between the low- and high-risk groups. Our analysis further implicated a cohort of genes-including LINC01559, C11orf86, SERPINB5, DSG3, MSLN, EREG, FAM83A, CXCL5, LY6D, and PSCA-as cardinal mediators in PAAD pathogenesis. A convergence of our predictive model with an analysis of CNVs, single nucleotide polymorphisms (SNPs), and drug sensitivities, revealed an intricate relationship with the FRGs. CONCLUSIONS: Our findings accentuate the salient role of FRGs as critical modulators in the pathogenesis and progression of PAAD. Importantly, our composite prognostic framework offers invaluable insights into PAAD clinical trajectory. Moreover, the complex crosstalk between FRGs and immune cell landscapes in the tumor microenvironment (TME) may elucidate prospective therapeutic strategies. The clinical translational utility of these insights, however, requires further in-depth empirical exploration. Accordingly, the FRG signature introduces a compelling new avenue for risk stratification and targeted therapeutic interventions in this devastating malignancy.