Researchers identified 25 ferroptosis-related genes that were differentially expressed in keloids. The findings provided new insights into keloid pathogenesis and potential therapeutic targets.
In a bioinformatics study, published in the Chinese Journal of Plastic and Reconstructive Surgery, the researchers identified 25 ferroptosis-related differentially expressed genes (FRDEGs) that may contribute to the development of keloids.
The researchers analyzed gene expression data from the Gene Expression Omnibus database, comparing 4 keloid and 3 normal skin samples. Among the 1,475 differentially expressed genes identified (log2 fold change > 1, P < .05), 25 were related to ferroptosis based on the FerrDb database. These included eight upregulated and 17 downregulated genes in keloids.
Further, 10 hub FRDEGs were identified using protein-protein interaction network analysis: PLA2G6, RARRES2, SNCA, CYP4F8, CDKN2A, ALOX12, FABP4, ALOX12B, NEDD4, and NEDD4L. RT-qPCR validation in 3 keloid and 3 normal skin samples confirmed significantly reduced expression of ALOX12 (P < .0001), ALOX12B (P < .01), and CYP4F8 (P < .01) in keloids.
Gene Ontology enrichment analysis revealed that the unsaturated fatty acid metabolic process, fatty acid transport, response to iron ion, arachidonic acid metabolic process, and cellular response to oxidative stress were among the top enriched biological processes for the FRDEGs (adjusted P < .05).
KEGG pathway analysis showed upregulation of the Hippo and p53 signaling pathways and downregulation of the PPAR signaling pathway, glutathione metabolism, and arachidonic acid metabolism in keloids (adjusted P < .05). Gene set enrichment analysis further highlighted the downregulation of unsaturated fatty acid (normalized enrichment score [NES] = –1.50, P = .004), fatty acid (NES = –1.47, P = .015), and lipid metabolic processes (NES = –1.34, P = .015).
A miRNA-FRDEG interaction network predicted hsa-mir-155-5p (16 edges), hsa-let-7b-5p (14 edges), hsa-mir-124-3p (8 edges), hsa-mir-145-5p (8 edges), hsa-mir-328-3p (6 edges), hsa-mir-24-3p (5 edges), and hsa-mir-10b-5p (5 edges) as key miRNA regulators. Enrichment analysis of these miRNAs highlighted their involvement in transcription factor activity, protein serine/threonine kinase activity, and signaling pathways such as VEGF, ErbB, and TRAIL (P < .05).
The study had limitations, including a small sample size and the need for further experimental validation. However, the results suggested that dysregulation of ferroptosis-related genes and pathways, particularly those involved in unsaturated fatty acid metabolism, may contribute to the uncontrolled fibroblast proliferation and collagen deposition characteristic of keloids. The identified genes and pathways represent potential targets for future research and therapeutic development.
The authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the research.
