Regulation of ferroptosis in colorectal cancer through therapeutic modulation and miRNA targeting

Colorectal cancer (CRC) is a highly prevalent disease that represents a major global health burden. Ferroptosis has gained significant attention in recent years as a potential target for cancer therapy. Meanwhile, microRNAs (miRNAs) have emerged as key regulators of gene expression, with the potential to influence various cellular pathways and functions, including those involved in cancer development and treatment. In this study, we employed a systems biology approach to leverage the FerrDb database and to identify key genes involved in the ferroptosis pathway. Then, we utilized the NCBI Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) associated with ferroptosis in CRC. The miRNet platform was used to identify miRNAs that target ferroptosis-associated genes in CRC. Additionally, we explored the Therapeutic Target Database (TTD) and Drug Gene Interaction Database (DGIdb) to identify approved drugs that could potentially modulate the identified targets. Our analysis identified EZH2, G6PD, PARP1, RRM2, SCD, and SLC7A11 as key suppressor genes that are dysregulated in CRC and are also recognized as approved drug targets. Furthermore, we identified hsa-miR-423-5p, hsa-miR-93-5p, hsa-miR-15a-5p, miR-103a-3p, and hsa-miR-16-5p as the five top miRNAs that show the highest number of connections to genes involved in the ferroptosis pathway. Interestingly, we also found that medications such as prasterone, tazemetostat, isoxyl, gemcitabine, ponsegromab, scx-2023, and nicotinamide could potentially be used in combination with the identified miRNAs to target ferroptosis in CRC. To further validate the stability and reliability of the predicted protein-ligand interactions, molecular dynamics (MD) simulations and MM-PBSA analyses were performed on selected top-ranking complexes, which confirmed their stable and favorable binding and supported the robustness of our docking results. These findings suggest that targeting these miRNAs and their associated genes, along with using the identified drugs, could be a promising strategy for CRC treatment, leveraging the potential of ferroptosis-inducing therapies.