Gut microbiota-bile acid crosstalk contributes to calcium oxalate nephropathy through Hsp90α-mediated ferroptosis
The gut microbiota and its metabolites have been implicated in calcium oxalate (CaOx) nephrolithiasis, while the precise mechanism remains unclear. We report that the gut microbiota dysbiosis in patients with CaOx nephrolithiasis results in an elevated level of deoxycholic acid (DCA) and diminished presence of Faecalibacterium prausnitzii. DCA correlates positively with urinary oxalate excretion and stone burden and inversely with F. prausnitzii abundance. Administration of F. prausnitzii to high-oxalate-diet mice alleviates renal CaOx crystal deposition by reducing DCA and secondary bile acid production. DCA impairs intestinal oxalate catabolism, enhances CaOx crystal adhesion to renal tubular epithelial cells via Hsp90α upregulation, activates the Hsp90α/Nrf2/HO-1 pathway, and induces Gpx4 degradation by Hsp90α interaction and ubiquitination, resulting in ferrous ion accumulation, lipid peroxidation, and ferroptosis to facilitate renal injury and CaOx crystal deposition. These data highlight the important role of gut microbiota-bile acid crosstalk in the pathogenesis of CaOx nephrolithiasis.
Authors
- Liyuan Xiang (ORCID: https://orcid.org/0000-0001-8223-6997)
- Banghua Liao (ORCID: https://orcid.org/0000-0002-1017-4990)
- Kunjie Wang (ORCID: https://orcid.org/0000-0001-8289-2791)
- Linhu Liu (ORCID: https://orcid.org/0000-0001-5253-6649)
- Zhongyu Jian (ORCID: https://orcid.org/0000-0002-8532-9336)
- Yu Liu (ORCID: https://orcid.org/0000-0002-1193-7830)
- Jingwen Wei (ORCID: https://orcid.org/0000-0001-9185-3604)
- Xi Jin (ORCID: https://orcid.org/0000-0003-2624-1323)
- Lede Lin (ORCID: https://orcid.org/0000-0003-0185-6823)
- Shiqian Qi (ORCID: https://orcid.org/0000-0002-7589-8877)
- Yiqiong Yuan
- Ya Li (ORCID: https://orcid.org/0000-0001-7246-2069)
- Jiawei Chen (ORCID: https://orcid.org/0000-0003-1381-3046)
- Jun Wen
- Mengzhu Yang (ORCID: https://orcid.org/0009-0004-8694-1801)
- Menghua Wang (ORCID: https://orcid.org/0000-0003-2670-6434)
- Yucheng Ma (ORCID: https://orcid.org/0000-0001-8456-5479)
Institutions
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115936
- Citations
- 5
- Primary Topic
- Colorectal Cancer Screening and Detection
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- National Natural Science Foundation of China
- Department of Science and Technology of Sichuan Province