G6PC Downregulation Promotes Renal Calcium Oxalate Stone Formation via Lactate‐Induced SNAIL1 K206 Lactylation and Epithelial‐Mesenchymal Transition
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.
Authors
- K Liu
- Zhenzhen Xu (ORCID: https://orcid.org/0000-0003-4111-3530)
- Xiongmin Mao (ORCID: https://orcid.org/0000-0002-6026-9904)
- Ninghan Feng (ORCID: https://orcid.org/0000-0002-0892-6102)
- Youmiao Zeng (ORCID: https://orcid.org/0009-0001-2902-6533)
- Hui Li (ORCID: https://orcid.org/0000-0001-9198-3951)
- Mengcheng Luo (ORCID: https://orcid.org/0000-0001-7058-5911)
- Ruixin Fan (ORCID: https://orcid.org/0000-0002-1779-2986)
- Yangjun Zhang (ORCID: https://orcid.org/0000-0003-1070-6210)
- Yue Wang (ORCID: https://orcid.org/0000-0003-0098-5359)
- Xinyu Xu (ORCID: https://orcid.org/0000-0002-5040-0171)
- H B Wu (ORCID: https://orcid.org/0000-0002-0721-9596)
- Xiangyang Yao
- H X Xu
- Boming Zhang
- Chen Duan
- Bo Li
Institutions
- Jiangnan University (CN)
- University of Science and Technology of China (CN)
- Wuhan University (CN)
- Wuhan Business University (CN)
- Shandong Mental Health Center (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Shandong Provincial QianFoShan Hospital (CN)
- Tongji Hospital (CN)
- Shandong First Medical University (CN)
- Shenzhen Second People's Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-05-10
- DOI
- https://doi.org/10.1002/advs.75585
- Primary Topic
- Kidney Stones and Urolithiasis Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hubei Province