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.