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journal article·2026-05-10Open access

G6PC Downregulation Promotes Renal Calcium Oxalate Stone Formation via Lactate‐Induced SNAIL1 K206 Lactylation and Epithelial‐Mesenchymal Transition

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

Advanced Science
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Abstract

ABSTRACT 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.
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Research context

Materials processing

OpenAlex topics: Kidney Stones and Urolithiasis Treatments · Parathyroid Disorders and Treatments · Biomedical Research and Pathophysiology

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Affiliations

Department of Urology Zhongnan Hospital of Wuhan University Wuhan Hubei China

Department of Urology The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital Jinan Shandong China

Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis Shandong Institute of Nephrology Jinan Shandong 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 Radiation and Medical Oncology 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

Taikang Center for Life and Medical Sciences Wuhan University Wuhan Hubei China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Hubei Province

References (38)

Show source-provided references
1. 10.1038/nrdp.2016.810.1038/nrdp.2016.8 ↗
2. 10.1016/j.juro.2014.05.11710.1016/j.juro.2014.05.117 ↗
3. 10.1016/j.juro.2012.11.00410.1016/j.juro.2012.11.004 ↗
4. 10.1097/js9.000000000000341710.1097/js9.0000000000003417 ↗
5. 10.1038/s41581‐019‐0216‐610.1038/s41581‐019‐0216‐6 ↗
6. 10.1681/asn.202105068010.1681/asn.2021050680 ↗
7. 10.1016/j.phrs.2022.10652410.1016/j.phrs.2022.106524 ↗
8. 10.1038/s41581‐024‐00836‐y10.1038/s41581‐024‐00836‐y ↗
9. 10.1016/j.kint.2023.08.00610.1016/j.kint.2023.08.006 ↗
10. 10.1002/advs.20241393710.1002/advs.202413937 ↗
11. 10.1038/s41586‐019‐1678‐110.1038/s41586‐019‐1678‐1 ↗
12. 10.1016/j.kint.2017.09.03310.1016/j.kint.2017.09.033 ↗
13. 10.1039/c4tb01626b10.1039/c4tb01626b ↗
14. 10.1016/j.exger.2024.11260910.1016/j.exger.2024.112609 ↗
15. 10.1038/s41467‐023‐38975‐810.1038/s41467‐023‐38975‐8 ↗
16. 10.1186/s40164‐022‐00320‐y10.1186/s40164‐022‐00320‐y ↗
17. 10.2174/1568009611313666010210.2174/15680096113136660102 ↗
18. 10.1126/sciadv.adc946510.1126/sciadv.adc9465 ↗
19. 10.1155/2021/883635510.1155/2021/8836355 ↗
20. 10.1111/j.1476‐5381.2011.01242.x10.1111/j.1476‐5381.2011.01242.x ↗
21. 10.1681/asn.000000000000042110.1681/asn.0000000000000421 ↗
22. 10.1016/j.ijsu.2016.11.02310.1016/j.ijsu.2016.11.023 ↗
23. 10.1155/2021/727796610.1155/2021/7277966 ↗
24. 10.1016/j.redox.2024.10324610.1016/j.redox.2024.103246 ↗
25. 10.1002/advs.20250706810.1002/advs.202507068 ↗
26. 10.3389/fncel.2025.163618510.3389/fncel.2025.1636185 ↗
27. 10.1002/mco2.7042110.1002/mco2.70421 ↗
28. 10.3389/fcvm.2025.164488610.3389/fcvm.2025.1644886 ↗
29. 10.1038/s41418‐025‐01554‐z10.1038/s41418‐025‐01554‐z ↗
30. 10.1016/j.phymed.2024.15632410.1016/j.phymed.2024.156324 ↗
31. 10.1002/advs.20230721610.1002/advs.202307216 ↗
32. 10.1007/s00018‐024‐05427‐510.1007/s00018‐024‐05427‐5 ↗
33. 10.3390/jcm806075710.3390/jcm8060757 ↗
34. 10.3389/fimmu.2021.72420010.3389/fimmu.2021.724200 ↗
35. 10.1186/s40170‐024‐00362‐210.1186/s40170‐024‐00362‐2 ↗
36. 10.3724/abbs.202307410.3724/abbs.2023074 ↗
37. 10.1002/advs.20240894510.1002/advs.202408945 ↗
38. 10.1016/j.ijbiomac.2024.13766810.1016/j.ijbiomac.2024.137668 ↗