Li J, Cao MX, Wang JM, Zheng YY, Que RY, Lin LB. Saikosaponin-d alleviates hepatic stellate cell activation and liver fibrosis by inhibiting the TGF-β1/Smads signaling pathway and blocking the EMT process. World J Hepatol 2026; 18(5): 116712 [DOI: 10.4254/wjh.v18.i5.116712]
Corresponding Author of This Article
Ren-Ye Que, Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, No. 230 Baoding Road, Shanghai 200082, China. 824492@qq.com
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Gastroenterology & Hepatology
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Li J, Cao MX, Wang JM, Zheng YY, Que RY, Lin LB. Saikosaponin-d alleviates hepatic stellate cell activation and liver fibrosis by inhibiting the TGF-β1/Smads signaling pathway and blocking the EMT process. World J Hepatol 2026; 18(5): 116712 [DOI: 10.4254/wjh.v18.i5.116712]
World J Hepatol. May 27, 2026; 18(5): 116712 Published online May 27, 2026. doi: 10.4254/wjh.v18.i5.116712
Saikosaponin-d alleviates hepatic stellate cell activation and liver fibrosis by inhibiting the TGF-β1/Smads signaling pathway and blocking the EMT process
Jing Li, Meng-Xing Cao, Jun-Min Wang, Yi-Yuan Zheng, Ren-Ye Que, Liu-Bing Lin
Jing Li, Department of Nursing, The People’s Hospital of Yubei District of Chongqing, Chongqing 401120, China
Meng-Xing Cao, Jun-Min Wang, Yi-Yuan Zheng, Liu-Bing Lin, Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
Ren-Ye Que, Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
Co-first authors: Jing Li and Meng-Xing Cao.
Co-corresponding authors: Ren-Ye Que and Liu-Bing Lin.
Author contributions: Li J performed the research; Cao MX wrote this manuscript; Li J and Cao MX contributed equally to this manuscript as co-first authors; Wang JM and Zheng YY helped revise this manuscript; Que RY designed the research study; Lin LB provided financial support for this research; Que RY and Lin LB contributed equally to this manuscript as co-corresponding authors. All authors approved final revision of the paper.
AI contribution statement: AI tool was used solely for language editing and translation support. ChatGPT assisted in improving the clarity and grammar of the English text. The scientific content, data analysis, interpretation, and conclusions were developed entirely by the authors. The authors reviewed and approved all AI-assisted modifications and assume full responsibility for the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82304932; and Traditional Chinese Medicine Research Project of Shanghai Municipal Health Commission, No. 2022QN051.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (approval No. 2024018).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Corresponding author: Ren-Ye Que, Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, No. 230 Baoding Road, Shanghai 200082, China. 824492@qq.com
Received: November 19, 2025 Revised: December 17, 2025 Accepted: March 12, 2026 Published online: May 27, 2026 Processing time: 189 Days and 1.9 Hours
Abstract
BACKGROUND
Liver fibrosis is a compensatory response to chronic liver injuries, such as viral hepatitis, alcohol abuse, and metabolic disorders. Despite this, no United States Food and Drug Administration-approved anti-fibrotic drugs are currently available. Saikosaponin-d (SSd) has demonstrated antifibrotic effects, but its impact on the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway and epithelial-mesenchymal transition (EMT) during fibrosis remains poorly understood.
AIM
To investigate the effect of SSd on the TGF-β1/Smads signaling pathway and EMT during hepatic fibrosis progression.
METHODS
A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 mice (CCl4: olive oil = 1:4, twice weekly for 6 weeks). Mice were assigned to control, CCl4, and SSd + CCl4 groups with SSd administered intraperitoneally (1.5 mg/kg) for 6 weeks. The human hepatic stellate cell line LX-2 was activated with TGF-β1, and groups included control, TGF-β1, and TGF-β1 + SSd. The TGF-β1 group was treated with TGF-β1 (5 ng/mL), while the TGF-β1 + SSd group received both TGF-β1 (5 ng/mL) and SSd (5 μmol/L) for 24 hours. Evaluations included serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver histology (Masson’s trichrome, Sirius red staining), α-smooth muscle actin immunohistochemistry, cell counting kit-8 cell viability assay, quantitative real-time polymerase chain reaction, and western blotting to assess the effects of SSd on TGF-β1/Smads signaling and EMT.
RESULTS
SSd alleviated liver injury in CCl4-induced fibrotic mice, significantly reducing serum ALT, AST levels, and collagen fiber deposition (P < 0.05). Importantly, SSd significantly decreased mRNA, α-smooth muscle actin, p-Smad2, TGF-β1, and p-Smad3 levels in fibrotic liver tissue (P < 0.05). Regarding EMT, SSd reduced the protein levels of N-cadherin and vimentin, while increasing E-cadherin expression (P < 0.05). SSd inhibited TGF-β1-induced LX-2 cell proliferation and decreased ALT and AST levels (P < 0.05). Moreover, it significantly suppressed the levels of key molecules in the TGF-β1/Smads pathway and EMT progression in vitro (P < 0.05).
CONCLUSION
SSd mitigates hepatic stellate cell activation and liver fibrosis progression by inhibiting the TGF-β1/Smads signaling pathway and effectively blocking the EMT process. These findings position SSd as a promising therapeutic agent and potential antifibrotic strategy.
Core Tip: Saikosaponin-d (SSd) is a promising therapeutic agent and potential antifibrotic drug. This study, through in vivo and in vitro models, demonstrates that SSd alleviates hepatic stellate cell activation and liver fibrosis progression by inhibiting the transforming growth factor-β1/Smads signaling pathway and effectively blocking the epithelial-mesenchymal transition process. The study also addresses the reversibility and safety issues of SSd, proposing solutions. These findings enrich the understanding of SSd’s antifibrotic molecular mechanisms and provide a theoretical basis for drug optimization and improvement.
