Decrypting the impact of ferroptosis and cuproptosis in development of pancreatic ductal adenocarcinoma.

Pancreatic cancer (PanCa) is a devastating disease with very low survival rate. Ferroptosis and cuproptosis, regulated forms of cell death, resulting from the accumulation of iron and copper ions, respectively are gaining increasing attention for their roles in tumor development. These non-apoptotic cell death forms would be worth to explore in the context of PanCa, as it is a difficult disease to treat and often become resistant to apoptosis inducing conventional therapeutic modes. So, targeting the transcription factors (TFs) regulating both these cell death pathways are critical for pancreatic ductal adenocarcinoma (PDAC) therapeutics because they control the cellular mechanisms that execute these specialized, non-apoptotic forms of cell death. Therefore, using differentially expressed genes (DEGs) from RNA-Seq and TCGA data, we first rebuilt the protein-protein interaction network (PPIN) for PDAC (PPIN). We then identified 71 strongly connected clusters within the PPIN. Functional enrichment of these clusters revealed that key cell death mechanisms are compromised in this cancer. Next, we discovered that 37 deregulated clusters of PDAC are regulated by 10 ferroptotic and 1 cuproptotic transcription factors (FerrTFs and CuprTF), respectively. NFE2L2 was found to be both FerrTF and CuprTF. Using various clinicopathological parameters for PDAC, we screened 4 critical TFs among the 10 TFs viz. NFE2L2, TP53, ZEB1, and HIF1A which might be critical for disease progression. Lastly, drugs epigallocatechin gallate (EGCG) and protodioscin (PTN) were identified as promising therapeutic candidates against the 4 TFs using molecular docking and simulation studies. This preliminary investigation pinpoints possible TFs of ferroptosis and cuproptosis in PDAC and develops countermeasures against them.