Ferroptosis-related genes in small intestinal NETs

The study focused on identifying ferroptosis-related genes in small intestinal neuroendocrine neoplasms (SI-NENs) and their diagnostic and therapeutic potential. Ferroptosis, an iron-dependent cell death mechanism, was analyzed using bioinformatics and machine learning on RNA sequencing datasets (GSE65286 and GSE98894). Researchers identified four key genes: CDCA3, CDC25A, CYP4F8, and MYB, which were experimentally validated using tissue samples from 10 healthy individuals and 14 SI-NEN patients.

Among these genes, CYP4F8 and CDCA3 were significantly downregulated in SI-NEN tumor tissues, suggesting their role as tumor suppressors. Lower expression of these genes was associated with higher tumor grades (G2/G3) and aggressiveness, indicating their potential involvement in tumor progression. Importantly, CYP4F8 showed a strong negative correlation with Ki67 (proliferation marker) and tumor size, linking its reduced expression to increased malignancy.

Gene Set Enrichment Analysis (GSEA) revealed upregulation of cancer-related and metabolic pathways tied to ferroptosis. Functional analysis highlighted pathways like ferroptosis, PPAR signaling, and transcriptional misregulation, which regulate lipid metabolism and oxidative stress. Diagnostic accuracy was demonstrated with Receiver Operating Characteristic (ROC) analysis, showing all four genes had AUC values above 0.9, confirming their potential as biomarkers.

Histological validation confirmed reduced protein levels of CYP4F8 and CDCA3 in SI-NEN tissues. Molecular docking suggested therapeutic potential, with drugs like daunorubicin and quercetin showing strong binding affinity to these genes. Despite promising findings, larger multi-center studies are needed to further validate these genes as biomarkers and therapeutic targets for SI-NENs.