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Pharmaceuticals
Volume 19
Issue 1
10.3390/ph19010015
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways

by
Qicheng Guo
1,†,
Lianye Peng
1,†,
Jingyi Zhang
1,
Junming Hu
1,
Yinyin Wang
2,
Jiali Wei
3,* and
Zhihao Zhang
1,*
1
Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
2
State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
3
Department of Nephrology, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou 470100, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceuticals 2026, 19(1), 15; https://doi.org/10.3390/ph19010015 (registering DOI)
Submission received: 13 November 2025 / Revised: 13 December 2025 / Accepted: 16 December 2025 / Published: 21 December 2025
(This article belongs to the Special Issue Novel Drug Candidates for the Treatment of Cardiac and Renal Diseases)
Review Reports Versions Notes

Abstract

Background/Objectives: To explore the protective effects of 7-Ketolithocholic acid (7-KLCA) against renal fibrosis and its mechanism, focusing on its interaction with farnesoid X receptor (FXR). Methods: In vitro, TGF-β-induced fibrosis in HK-2/NRK-49F cells and LPS-induced inflammation in HK-2 cells were detected by CCK-8, Western blot, and qPCR. In vivo, unilateral ureteral obstruction (UUO) and adenine (Ade)-induced mouse models were treated with a low/high-dose 7-KLCA or losartan. Renal injury was evaluated via H&E/Masson staining, serum creatinine (SCR), and blood urea nitrogen (BUN) levels. The 7-KLCA-FXR interaction was verified by molecular docking, CETSA, and DARTS. FXR downstream genes and related proteins were measured by WB and qPCR. Results: 7-KLCA inhibited the expression of fibrotic proteins (fibronectin, collagen-I) and reduced the LPS-induced release of inflammatory factors (IL-1β, IL-6). In mice, it alleviated renal swelling, collagen deposition, and tubular damage, while lowering serum SCR and BUN levels. Mechanistically, 7-KLCA stably bound to the FXR ligand-binding domain, enhanced its thermal stability and degradation resistance. It upregulated FXR and its downstream genes SHP and FGF15, thereby inhibiting the activation of TGF-β/Smad and Wnt/β-catenin pathways. Conclusions: This is the first study to clarify the molecular mechanism through which 7-KLCA targets FXR and dually suppresses the key pro-fibrotic pathways TGF-β/Smad and Wnt/β-catenin, thereby exerting anti-renal fibrosis effects.
Keywords: renal fibrosis; FXR; 7-KLCA; TGF-β/Smad pathway; Wnt/β-catenin pathway renal fibrosis; FXR; 7-KLCA; TGF-β/Smad pathway; Wnt/β-catenin pathway

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MDPI and ACS Style

Guo, Q.; Peng, L.; Zhang, J.; Hu, J.; Wang, Y.; Wei, J.; Zhang, Z. 7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways. Pharmaceuticals 2026, 19, 15. https://doi.org/10.3390/ph19010015

AMA Style

Guo Q, Peng L, Zhang J, Hu J, Wang Y, Wei J, Zhang Z. 7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways. Pharmaceuticals. 2026; 19(1):15. https://doi.org/10.3390/ph19010015

Chicago/Turabian Style

Guo, Qicheng, Lianye Peng, Jingyi Zhang, Junming Hu, Yinyin Wang, Jiali Wei, and Zhihao Zhang. 2026. "7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways" Pharmaceuticals 19, no. 1: 15. https://doi.org/10.3390/ph19010015

APA Style

Guo, Q., Peng, L., Zhang, J., Hu, J., Wang, Y., Wei, J., & Zhang, Z. (2026). 7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways. Pharmaceuticals, 19(1), 15. https://doi.org/10.3390/ph19010015

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