The Dual Role of Saikosaponins in Liver Disease Treatment: A Comprehensive Review of Pharmacological Activities and Toxicological Characteristics.

Liver diseases, including viral hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), remain major global health burdens due to their high prevalence and limited therapeutic options. The need for safer and more effective hepatoprotective agents has renewed interest in traditional herbal medicines such as Radix Bupleuri. Its major bioactive constituents, saikosaponins (SSs), exhibit diverse pharmacological activities. This review synthesizes recent advances in the pharmacodynamics, molecular mechanisms, and toxicological characteristics of SSs, emphasizing their dual hepatoprotective and hepatotoxic properties. Relevant literature published from 2000 to 2025 was systematically retrieved from major scientific databases, including PubMed, Web of Science, Google Scholar, and other sources as appropriate, with emphasis on mechanistic studies and in vitro/in vivo evidence. SSs exert hepatoprotective effects through multiple mechanisms, including inhibition of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, activation of nuclear receptors, induction of hepatic stellate cell apoptosis and autophagy, and modulation of lipid metabolism via peroxisome proliferator-activated receptor α (PPARα)/sterol regulatory element-binding protein 1c (SREBP1c) signaling. SSs in HCC inhibit Cyclooxygenase-2 and STAT3, promote apoptosis and ferroptosis, suppress angiogenesis, and enhance chemotherapy and radiotherapy sensitivity. However, accumulating evidence indicates that SSs may induce dose-dependent hepatotoxicity through oxidative stress, apoptosis and autophagy injury. These dual pharmacological effects are influenced by CYP regulation, bioavailability, and potential drug-drug interactions. Overall, SSs represent promising yet complex therapeutic candidates. Optimization of dosing strategies, clarification of mechanistic determinants, and development of advanced delivery systems are essential for their safe clinical translation. Future research should incorporate multi-omics approaches, physiologically relevant liver models, and rigorously designed clinical trials to establish standardized Saikosaponin-based therapies for liver diseases.