Lin Huagang, Nie Linjing, Wu Deping, Zhang Dexian, Peng Rui, Tao Sijie, Ye Zhibin, Zhu Sibo, Ye Maoqing, Xiao Jing
Department of Nephrology, Huadong Hospital, Fudan University, Shanghai, PR China.
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, PR China.
Commun Biol. 2025 Jun 2;8(1):845. doi: 10.1038/s42003-025-08303-5.
Decreased renal uric acid excretion is a major contributor to hyperuricemia (HUA), but its underlying mechanism remains unclear. Here, we identify cathepsin B (CTSB) as a key regulator of urate handling in HUA. Urinary CTSB levels were elevated in HUA patients, and renal CTSB expression was increased in HUA mice. In CTSBmice, the expression of reabsorptive urate transporters URAT1 and GLUT9 was decreased, while the secretory transporter ABCG2 was upregulated, leading to enhanced renal uric acid excretion and reduced serum uric acid (SUA). CTSB deficiency also reduced serum IL-1β, IL-6, and TNF-α levels. In vitro and transcriptomic analyses revealed that CTSB inhibition suppressed glycolysis-marked by reduced HK2 and PKM2 expression-downregulated URAT1 and GLUT9, and upregulated ABCG2. Conversely, CTSB overexpression enhanced glycolysis and reversed these effects. These findings suggest that CTSB promotes urate retention via glycolysis and may serve as a novel target for HUA treatment.
肾尿酸排泄减少是高尿酸血症（HUA）的主要原因，但其潜在机制仍不清楚。在此，我们确定组织蛋白酶B（CTSB）是HUA中尿酸处理的关键调节因子。HUA患者尿CTSB水平升高，HUA小鼠肾CTSB表达增加。在CTSB基因敲除小鼠中，重吸收性尿酸转运体URAT1和GLUT9的表达降低，而分泌性转运体ABCG2上调，导致肾尿酸排泄增加和血清尿酸（SUA）降低。CTSB缺乏还降低了血清IL-1β、IL-6和TNF-α水平。体外和转录组分析表明，CTSB抑制以HK2和PKM2表达降低为标志抑制糖酵解，下调URAT1和GLUT9，并上调ABCG2。相反，CTSB过表达增强糖酵解并逆转这些作用。这些发现表明，CTSB通过糖酵解促进尿酸潴留，可能成为HUA治疗的新靶点。
