Identification of ferroptosis-associated genes exhibited in human kidney biopsies after one hour of normothermic machine perfusion

Abstract Background In the 21st century, chronic kidney disease (CKD) has become a major global health problem, and the prevalence of end-stage kidney disease (ESKD) has increased rapidly worldwide. In patients with ESKD, transformative kidney transplantation technology offers the greatest potential for improving quality of life and increasing survival. A growing number of studies now suggest that normothermic machine perfusion (NMP) may be beneficial for graft preservation. Ferroptosis has been shown to have significant adverse effects in models of kidney ischemia-reperfusion injury. However, few studies have examined the effect of NMP on ferroptosis in transplanted kidneys. Method In the current study, gene expression profiles of pre-NMP and 1h-NMP of four discarded human kidney biopsies were downloaded from a public database, and 21 differentially expressed genes (DEGs) were identified using the Wilcoxon rank-sum test. These genes were screened for ferroptosis-associated genes using the FerrDb database, thereby identifying six genes. Finally, the construction of gene-microRNA (miRNA), gene transcription factor (TF), gene-disease, and gene-drug networks, in conjunction with gene ontology and biological pathway enrichment analysis, was used to inform hypothesis regarding the molecular mechanisms of NMP regulation of ferroptosis. Results Six genes were involved in NMP regulation of ferroptosis, including ATF3, TNFAIP3, JUN, IL6, CXCL2, and GDF15. Ferroptosis-associated genes are the key players in kidney tissue inflammatory responses and may be regulated by several identified miRNAs and TFs, thereby suggesting that the inhibition of ferroptosis by NMP may involve regulatory pathways. Conclusion These results suggest that 1 h of NMP treatment may inhibit ferroptosis in kidney tissue. This finding may help improve transplant kidney preservation methods and reduce transplant kidney injury and post-transplant kidney adverse events.