SOCS2 Downregulation Is Associated with a Ferro-Aging-Related Transcriptomic Signature in Proximal Tubular Cells in Chronic Kidney Disease

Objectives: This study aimed to identify ferro-aging-related hub genes in chronic kidney disease (CKD) and elucidate their potential roles in proximal tubular (PT) cells. Methods: Differential expression analysis was performed using GSE104954, and the differentially expressed genes were intersected with a set of ferro-aging-related genes. Feature selection was conducted using the least absolute shrinkage and selection operator (LASSO), support vector machine–recursive feature elimination (SVM-RFE), and random-forest algorithms. The findings were externally validated in GSE180394. Single-cell transcriptomic data from GSE183276 were then used to define the cellular localization and expression profile of the hub genes, and their regulatory networks were investigated using scTenifoldKnk-based in silico knockout and gene set enrichment analysis (GSEA). Results: Fourteen candidate genes were identified, of which IRF7 and SOCS2 were consistently selected by all three machine-learning algorithms. SOCS2 was significantly downregulated in both the discovery and validation cohorts and showed strong tissue-level discriminatory performance in the discovery cohort, with more modest performance in the external cohort. Single-cell analysis showed that SOCS2 downregulation occurred predominantly in PT cells; CKD PT cells also exhibited increased ACSL4 expression and the enrichment of the ferroptosis pathway. In silico SOCS2 knockout further identified 77 significantly perturbed genes, primarily associated with mitochondrial oxidative phosphorylation, oxidative stress, and metabolic homeostasis. Conclusions: Collectively, these findings identify SOCS2 as a candidate gene associated with a ferro-aging-related transcriptomic signature in CKD PT cells. The observed changes in ACSL4, ferroptosis-related pathways, mitochondrial oxidative phosphorylation, and oxidative stress networks are compatible with, but do not establish, a ferro-aging phenotype. Further functional validation is required to determine whether SOCS2 contributes causally to iron–lipid dysregulation and tubular injury in CKD.