Probucol inhibits palmitic acid-mediated renal calcium oxalate stone formation by targeting KLF5-PPARγ axis-mediated lipotoxicity

The pathogenesis of renal calcium oxalate (CaOx) stone is multifaceted and closely associated with metabolic disturbances. Palmitic acid (PA), a major saturated fatty acid, has emerged as a key contributor to CaOx stone formation. In this study, high-throughput drug screening identified probucol as a potential therapeutic agent capable of alleviating PA-mediated renal CaOx crystal formation in vitro and in vivo . Mechanistically, PA upregulates krüppel-like factor 5 (KLF5), which transcriptionally activates peroxisome proliferator activated receptor gamma (PPARγ) and thereby drives lipotoxicity. Probucol directly binds to arginine-440 (Arg440) within the zinc finger DNA-binding domain of KLF5, competitively inhibiting its DNA-binding ability. This inhibition suppresses PPARγ expression and mitigates PPARγ-mediated lipotoxicity. Collectively, our findings identify KLF5 as a novel intracellular target of probucol, and highlight its therapeutic potential in treating PA-mediated renal CaOx stone formation by mitigating lipotoxicity. • High-throughput screening identifies probucol as a potent inhibitor of PA-mediated renal calcium oxalate (CaOx) stone formation. • RNA-seq and bioinformatics analyses reveal that probucol suppresses PA-induced PPARγ expression, identifying the pathogenic role of PPARγ in benign kidney disease for the first time. • For the first time, probucol was found to directly bind to Arg440 in KLF5’s zinc finger domain, impairing its DNA-binding ability and thereby suppressing PA-induced KLF5 binding to the PPARγ promoter region, reducing PPARγ transcriptional activation • Inhibition of the KLF5–PPARγ axis by probucol alleviates PA-induced lipotoxicity to renal tubular epithelial cells, thereby reducing CaOx crystal adhesion and deposition • Clinical validation confirms PA-associated upregulation of KLF5 and PPARγ in patients with renal CaOx stone.