Identification and Computational validation of ferroptosis suppressor genes as therapeutic targets in pancreatic cancer

Pancreatic cancer remains one of the most lethal malignancies, characterised by aggressive progression, metabolic adaptation, and resistance to therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical mechanism influencing tumour survival and therapeutic response. However, the role of ferroptosis suppressor genes (FSGs) in pancreatic cancer remains incompletely understood. In this study, FSGs were systematically retrieved from FerrDb V2 and subjected to multi-step filtering to identify a curated set of 196 protein-coding genes. Genomic alteration analysis using cBioPortal across 21 pancreatic cancer studies (n = 5189 samples) identified seven recurrently altered genes (TP53, HSF1, PARP10, ZFP36, SIRT2, ECH1, and ENPP2) with alteration frequencies ≥ 3%. Co-occurrence analysis revealed predominantly cooperative alteration patterns among these genes, suggesting functional complementarity. Survival analysis demonstrated that alterations in FSGs were significantly associated with reduced overall survival in pancreatic cancer, with several genes (ECH1, ZFP36, SIRT2, and ENPP2) showing particularly strong adverse prognostic effects. In contrast, no significant survival associations were observed in oesophageal and gastric cancers, indicating a tumour-specific dependency on ferroptosis-related mechanisms. KEGG pathway enrichment analysis of the broader FSG set revealed significant involvement in pathways related to metabolic regulation (AMPK–mTOR signalling), autophagy, hypoxia response (HIF-1 signalling), and oncogenic signalling (PI3K–Akt pathway). Integration of these findings suggests that ferroptosis suppressor genes contribute to pancreatic cancer progression by promoting metabolic adaptation and resistance to oxidative stress. In conclusion, this study identifies key ferroptosis suppressor genes with prognostic relevance in pancreatic cancer and highlights their integration within critical metabolic and stress-response pathways. The tumour-specific nature of these associations underscores the importance of biological context and supports the potential of FSGs as prognostic biomarkers and potential therapeutic targets in ferroptosis-based strategies.