Multi-omics reveals that chenodeoxycholic acid promotes calcium oxalate kidney stone formation by targeting catalase

The aim of this study was to investigate the key bile acid metabolites and the target of action during calcium oxalate (CaOx) kidney stone formation using a multi-omics approach. CaOx kidney stone models in Sprague-Dawley (SD) rats were established by 1% ethylene glycol (EG). In CaOx kidney stone rat models, targeted metabolomics analysis revealed four differentially expressed bile acids in serum, and 11 differentially expressed bile acids in kidneys, and chenodeoxycholic acid (CDCA) was identified as the key metabolite in the formation of CaOx kidney stones. Transcriptomics of rat kidneys revealed 2,584 differentially expressed genes (DEGs), and proteomics analyses revealed 1,372 differentially expressed proteins (DEPs) between the control group and the CaOx group. Through combined transcriptomics, proteomics, and network pharmacology analysis, we identified catalase (CAT) as the key target of CDCA, with its expression and activity significantly lower in the CaOx group compared to the control group. Additionally, molecular docking analysis between CDCA and CAT showed potential interactions with a bonding energy of -8.764 kcal/mol, and both the mRNA and enzymatic activity of CAT were reduced in HK-2 and NRK-52E cells treated with oxalate and CDCA, indicating that CDCA may promote kidney stone formation by inhibiting CAT. This study reveals a new mechanism that CDCA promotes the formation of CaOx kidney stones by targeting CAT, providing a new perspective and potential target for the prevention and treatment of CaOx kidney stones.