Discovery of therapeutic agents targeting CKAP4 for kidney fibrosis using drug repositioning

Chronic kidney disease (CKD) characterized by the progressive loss of renal, represents a significant global health challenge. Central to CKD progression is kidney fibrosis, an irreversible process marked by the accumulation of extracellular matrix proteins. The development of effective antifibrotic therapies is thus crucial for improving patient outcomes. We conducted a comprehensive analysis of bulk RNA sequencing data from unilateral ureteral obstruction (UUO) and folic acid (FA)-induced nephropathy mice models, combined with single-cell RNA sequencing (scRNA-seq) to explore cellular heterogeneity and molecular mechanisms of kidney fibrosis. Differential gene expression analysis, gene co-expression network (CN) analysis, time-series clustering, and cell marker analysis were employed to identify core fibrosis-related genes. Our analyses revealed a set of 37 core fibrosis-related genes which are largely associated with inflammation and immune response and contributed to the production of extracellular matrix (ECM), with Ckap4 standing out as a key marker of kidney fibrosis. In vivo experiments demonstrated that knockdown of Ckap4 significantly reduced kidney fibrosis in UUO mice, as evidenced by decreased collagen deposition and improved renal function. Additionally, the repurposed small molecule drugs, especially CGP-60474, showed promising antifibrotic effects, further highlighting the potential of Ckap4 as a therapeutic target.