The high recurrence rate of cystine lithiasis observed in cystinuria patients highlights the need for new therapeutic options to address this chronic disease. There is growing evidence of an antioxidant defect in cystinuria, which has led to test antioxidant molecules as new therapeutic approaches. In this study, the antioxidant l-Ergothioneine was evaluated, at two different doses, as a preventive and long-term treatment for cystinuria in the Slc7a9^−/− mouse model. l-Ergothioneine treatments decreased the rate of stone formation by more than 60% and delayed its onset in those mice that still developed calculi. Although there were no differences in metabolic parameters or urinary cystine concentration between control and treated mice, cystine solubility was increased by 50% in the urines of treated mice. We also demonstrate that l-Ergothioneine needs to be internalized by its transporter OCTN1 (Slc22a4) to be effective, as when administrated to the double mutant Slc7a9^−/−Slc22a4^−/− mouse model, no effect on the lithiasis phenotype was observed. In kidneys, we detected a decrease in GSH levels and an impairment of maximal mitochondrial respiratory capacity in cystinuric mice that l-Ergothioneine treatment was able to restore. Thus, l-Ergothioneine administration prevented cystine lithiasis in the Slc7a9^−/− mouse model by increasing urinary cystine solubility and recovered renal GSH metabolism and mitochondrial function. These results support the need for clinical trials to test l-Ergothioneine as a new treatment for cystinuria.

在胱氨酸尿症患者中观察到的胱氨酸结石病的高复发率突出表明需要新的治疗方案来解决这种慢性疾病。越来越多的证据表明胱氨酸尿症存在抗氧化缺陷，这导致测试抗氧化分子作为新的治疗方法。在这项研究中，评估了两种不同剂量的抗氧化剂l-麦角硫因作为Slc7a9 ^−/−小鼠模型中胱氨酸尿症的预防和长期治疗作用。 l-麦角硫因治疗可将结石形成率降低 60% 以上，并延迟那些仍出现结石的小鼠的发病时间。尽管对照小鼠和治疗小鼠之间的代谢参数或尿胱氨酸浓度没有差异，但治疗小鼠尿液中胱氨酸的溶解度增加了 50%。我们还证明， l-麦角硫因需要被其转运蛋白 OCTN1 ( Slc22a4 ) 内化才能有效，因为当给予双突变体Slc7a9 ^−/− Slc22a4 ^−/−小鼠模型时，没有观察到对结石表型的影响。在肾脏中，我们检测到胱氨酸尿小鼠的谷胱甘肽水平下降，最大线粒体呼吸能力受损，而l-麦角硫因治疗能够恢复。因此， l-麦角硫因通过增加尿胱氨酸溶解度来预防Slc7a9 ^-/−小鼠模型中的胱氨酸结石，并恢复肾GSH代谢和线粒体功能。 这些结果支持需要进行临床试验来测试l-麦角硫因作为胱氨酸尿症的新疗法。