Nephrolithiasis is increasingly prevalent worldwide. Although metabolic dysregulation has emerged as an important feature of the disease, the specific metabolic programs within tubular epithelial cells that drive stone formation remain poorly understood. Here, we use single-cell transcriptomics to profile mouse models of nephrolithiasis and identify a marked suppression of gluconeogenesis in renal proximal tubular epithelial cells, driven by downregulation of the rate-limiting enzyme glucose-6-phosphatase (G6PC) and associated with lactate accumulation. We further show that loss of G6PC or lactate accumulation is sufficient to activate TGF-β/SMAD3 signaling, driving epithelial-mesenchymal transition (EMT) and a profibrotic epithelial program associated with enhanced crystal deposition. Mechanistically, lactate induces lactylation of the transcription factor SNAIL1 at lysine 206, facilitating its nuclear localization and transcriptional activation of TGF-β. Together, these findings establish a G6PC-lactate-SNAIL1 axis linking metabolic dysregulation to epithelial remodeling during nephrolithiasis.
Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026 May 10 [Epub ahead of print]
Kai Liu, Boming Zhang, Ruixin Fan, Chen Duan, Yangjun Zhang, Huahui Wu, Xiangyang Yao, Xiongmin Mao, Bo Li, Youmiao Zeng, Zhenzhen Xu, Yang Wang, Mengcheng Luo, Xinyu Xu, Ninghan Feng, Heng Li, Hua Xu
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Department of Urology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China., Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China., Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China., Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China., Department of Urology, Jiangnan University Medical Center, Wuxi, Jiangsu, China., School of Basic Medicine Science, Wuhan University, Wuhan, Hubei, China.