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

Haotian Ren; Yutong Chen; Yang Li; Jingdong Zhang; Yi Shao; Bangxian Yu; Linguo Xie; Shiyong Qi; Rui Wang; Zhiqun Shang; Chunyu Liu

doi:10.1016/j.jpha.2026.101575

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Haotian Ren, Yutong Chen, Yang Li, Jingdong Zhang, Yi Shao, Bangxian Yu, Linguo Xie, Shiyong Qi, Rui Wang, Zhiqun Shang, Chunyu Liu. Probucol inhibits palmitic acid-mediated renal calcium oxalate stone formation by targeting KLF5-PPARγ axis-mediated lipotoxicity[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101575

Citation:

Haotian Ren, Yutong Chen, Yang Li, Jingdong Zhang, Yi Shao, Bangxian Yu, Linguo Xie, Shiyong Qi, Rui Wang, Zhiqun Shang, Chunyu Liu. Probucol inhibits palmitic acid-mediated renal calcium oxalate stone formation by targeting KLF5-PPARγ axis-mediated lipotoxicity[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101575

Citation:

Haotian Ren, Yutong Chen, Yang Li, Jingdong Zhang, Yi Shao, Bangxian Yu, Linguo Xie, Shiyong Qi, Rui Wang, Zhiqun Shang, Chunyu Liu. Probucol inhibits palmitic acid-mediated renal calcium oxalate stone formation by targeting KLF5-PPARγ axis-mediated lipotoxicity[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101575

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

doi: 10.1016/j.jpha.2026.101575

Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 82470797 to Shiyong Qi, and 82400896 to Rui Wang), Tianjin Institute of Urology Talent Support Program (Grant Nos.: MYSRC202313 to Chunyu Liu, and MYSRC202411 to Linguo Xie), Clinical Medical Research Project of The Second Hospital of Tianjin Medical University (Grant No.: 2023LC01 to Chunyu Liu), and the Science and Technology Project of Tianjin (Grant No.: 25JCZDJC00380 to Chunyu Liu).

Received Date: Jun. 03, 2025
Accepted Date: Feb. 02, 2026
Rev Recd Date: Feb. 01, 2026
Available Online: Feb. 09, 2026

Abstract

Abstract

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.
- Renal calcium oxalate stone,
- Palmitic acid,
- Probucol,
- KLF5,
- PPARγ,
- Lipotoxicity

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References(50)

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