Multi-omics and machine learning reveal LYZ and ISG15 as diagnostic and therapeutic targets in autoimmune-mediated chronic kidney disease.

BACKGROUND: CKD represents a substantial worldwide health challenge, defined by the gradual development of tubulointerstitial fibrosis and reduced renal performance. Autoimmune-mediated factors are central to this pathological process, yet early diagnostic biomarkers and specific therapeutic targets are scarce. The objective of this research is to systematically pinpoint crucial specific genes that contribute to autoimmune-mediated CKD progression. METHODS: This study integrates transcriptomics, scRNA-seq, and machine learning to identify PTC-specific drivers in autoimmune-mediated CKD. Bulk RNA-seq (GSE180394, GSE104948) and scRNA-seq were analyzed using LASSO, Random Forest, Boruta, and MCODE algorithms to identify biomarkers, with performance validated via ROC, ANN, and nomograms. Nephroseq clarified gene correlations across CKD subtypes, while immune infiltration mapped microenvironmental interactions. An IRI mouse model validated targets and tested quercetin/all-trans retinoic acid (ATRA). RESULTS: Multi-algorithm integration robustly identified Lysozyme (LYZ) and Interferon-stimulated gene 15 (ISG15) as core diagnostic biomarkers for autoimmune-mediated CKD, yielding an Area Under the Curve of 0.957 in predictive nomograms and high accuracy (up to 97.7%) in ANN models. ISG15 and LYZ were found to be significantly upregulated in various autoimmune-mediated CKD subtypes according to the Nephroseq database analysis. Importantly, there was a strong positive correlation between their expressions (r = 0.5204, p < 0.0001) and a significant negative correlation with the glomerular filtration rate. Injured PTC subpopulations primarily showed upregulation of LYZ and ISG15, as dynamically localized by single-cell transcriptomics. Immune infiltration studies revealed that LYZ had a strong association with activated CD8+ T cells, while ISG15 was associated with activated dendritic cells. In vivo validation demonstrated that quercetin and ATRA successfully reversed the overexpression of LYZ and ISG15, and notably reduced renal fibrotic lesions, as shown by the decreased levels of α-SMA, Fibronectin, and Collagen I in IRI mice. CONCLUSION: LYZ and ISG15 are important diagnostic markers and collaborative agents in the development of kidney fibrosis in autoimmune-mediated CKD, with a strong correlation to the severity of the disease. Using agents like quercetin and ATRA to target the LYZ or ISG15 axis represents a promising precision medicine approach to slow the progression of CKD.