Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Abstract

Objective: To investigate the role of ferroptosis in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal injury. Methods: GSE104954 and GSE108112 were retrieved from the GEO database and concatenated into one dataset. Expression of ferroptosis-related genes (FRGs) was extracted for differential analysis. The ferroptosis signature genes were identified by LASSO regression and SVM-RFE, and their differential expression levels and diagnostic efficacy were verified by independent data sets. The ceRNA (miRNA-TF-mRNA) regulatory network and clinical diagnostic model were constructed respectively. By using consensus clustering, ferroptosis subtypes were identified. ssGSEA and GSVA were employed to assess immune response and pathway activation. Pan-cancer genes were found in TCGA and GTEx. Differential expression of CD44 in was validated by qPCR and immunohistochemistry from HPA database. Results:Twenty-four FRGs were differentially expressed in patients with AAV kidney injury. Furthermore, five ferroptosis signature genes were identified by two machine learning algorithms. Not only were differentially expressed in independent datasets, the clinical diagnostic model constructed by these genes provided reference for clinical decision-making, but also the ceRNA network revealed their complex regulatory mechanisms. Unsupervised clustering analysis discovered two ferroptosis subtypes with distinct gene expression, immunological microenvironment, and biological functioning pathways. Notably, CD44 was found to be closely associated with many immune cells, most immune responses, and HLA genes, as well as prognosis, immune cell infiltration, TMB, and MSI in patients with a variety of tumors, suggesting it may be a potential intervention target for human diseases including AAV renal injury and tumors. Conclusions:Ferroptosis in AAV with renal injury is significantly correlated with the immunological microenvironment. For AAV with renal injury and tumors, CD44 could be a useful intervention target.