# Exploring the involvement of ferroptosis-associated genes and pathways in mesenchymal stem cell aging through bioinformatics analysis

## TL;DR

This study explores how ferroptosis-related genes and pathways are involved in the aging of mesenchymal stem cells, identifying key genes that could help improve their regenerative abilities.

## Contribution

The study identifies key ferroptosis-related genes and pathways in aging mesenchymal stem cells and validates their roles using bioinformatics and experimental validation.

## Key findings

- 131 ferroptosis-related differentially expressed genes were identified in aging mesenchymal stem cells.
- Eight key genes, including ATF3, EZH2, and IL6, were consistently regulated across datasets and confirmed by qRT-PCR.
- These genes are involved in pathways like oxidative stress, lipid metabolism, and cellular senescence, suggesting their role in MSC aging.

## Abstract

Mesenchymal stem cells (MSCs) exhibit self-renewal and multipotent differentiation capabilities, and play roles in tissue repair and regeneration. However, age-related alterations can impair MSCs functions, potentially contributing to accelerated aging processes. Ferroptosis, a regulated form of cell death involving iron-mediated lipid peroxidation, is implicated in age-related diseases, although its specific role in MSCs aging remains unclear. Herein, the GSE68374 dataset was analyzed to obtain ferroptosis-related differentially expressed genes (FRDEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed, and potential drugs targeting FRDEGs were predicted. Protein-protein interaction (PPI) analysis was conducted and hub genes were identified, which were validated using two independent datasets. Furthermore, an integrated regulatory network of kinases, transcription factors (TFs), and microRNAs was constructed. A total of 131 FRDEGs were screened, which were involved in cellular responses to starvation, oxidative stress, lipid metabolism, cellular senescence, ferroptosis, and cancer pathways. Among twenty hub genes, eight key FRDEGs, including activating transcription factor 3 (ATF3), Enhancer of zeste homolog 2 (EZH2), synuclein alpha (SNCA), prostaglandin-endoperoxide synthase 2 (PTGS2), NADPH oxidase 4 (NOX4), cyclin-dependent kinase inhibitor 2A (CDKN2A), sequestosome 1 (SQSTM1), and interleukin 6 (IL6), were similarly regulated across external datasets, and the expression of these genes was also confirmed by qRT-PCR. These findings highlight the pivotal role of these genes in MSCs aging and ferroptosis, suggesting that targeting them could enhance MSCs regenerative capacity and mitigate the progression of aging-related alterations in MSCs.