An in-Depth Exploration of the Genetic Interaction Network Between Ferroptosis and Acute Pancreatitis

Background: Ferroptosis plays an important role in a variety of disease processes and is equally important in pancreatic diseases. However, the role of ferroptosis-related genes (FRGs) in acute pancreatitis (AP) remains unknown, and their specific potential mechanisms still need to be explored extensively.

Methods: AP-related gene microarray data were obtained from the GEO database, while FRGs were obtained from the Ferroptosis database (FerrDb). Differentially expressed genes (DEGs) were screened by the "limma" package, and GSEA was performed. The corresponding ferroptosis-related differentially expressed genes (FRDEGs) were screened, and GO and KEGG pathway analyses were performed. A PPI network was constructed to identify hub FRDEGs by CytoHubba, MCODE and CTD scores. Transcription factors and miRNAs predicted using the NetworkAnalyst database were used to establish the regulatory network. Immune cell infiltration analysis was performed by the R package "ssGSEA" algorithm. The hub genes were validated by transcriptome sequencing of AP model mice and immunohistochemistry in rats and mice.

Results: A total of 82 FRDEGs were screened, and these genes were mainly associated with Ferroptosis, hypoxic response, Autophagy, Mitophagy and immune inflammation. However, we also found that these genes are also jointly involved in other cell death modalities, such as Apoptosis and Necroptosis. Further analysis obtained 7 hub genes from 82 genes, and single-sample gene set enrichment analysis (ssGSEA) showed that the hub genes are closely associated with the infiltration of specific immune cells and the activation of immune pathways.

Conclusion: This study reveals the complex functions and important roles of ferroptosis-related genes in AP and provides gene targets for further studies of AP.

acute pancreatitis; autophagy; ferroptosis; inflammation; mitophagy.