Bupleurum: Saikosaponins and the Liver

Table of Contents

1. What Saikosaponins Are
2. Fatty Liver: The Mouse Evidence
3. Fibrosis and Cirrhosis
4. Hepatitis B: What the Trials Found
5. Liver Cancer
6. The Other Side: Liver Injury Reports
7. Protection and Toxicity: A Dose Question
8. Saikosaponins Beyond the Liver
9. Where the Liver Evidence Stands
10. What "Hepatoprotective" Usually Means in These Papers
11. Terms Used on This Page
12. Key Research Papers
13. Connections

What Saikosaponins Are

Saikosaponins are triterpene saponins: a rigid 30-carbon ring skeleton with chains of sugars attached. Like other saponins, they are partly water-loving and partly fat-loving, which lets them interact with cell membranes. A 2018 review in Phytomedicine names saikosaponins a, c and d as the major bioactive compounds of Radix Bupleuri and describes them as anti-inflammatory, anti-tumour, antioxidant, antiviral and hepatoprotective in research.

The same review, after examining 165 papers, added two important qualifications. Saikosaponins play "contradictory roles in the regulation of cell apoptosis, oxidative stress and liver fibrosis," and "increased risks of overdose-induced acute or accumulation-related chronic hepatotoxicity" of saikosaponins and the root "have also been reported." It also noted that how saikosaponins are metabolized, and what their breakdown products do, are "largely unknown."

A 2021 review focused on saikosaponin d called it both "the most antitumour component" and "the main toxic component" of the root, and listed its toxic effects as liver toxicity, nerve toxicity, haemolysis (bursting of red blood cells) and heart toxicity. It described the oral bioavailability of saikosaponin d (how much reaches the blood when swallowed) as "still controversial."

Fatty Liver: The Mouse Evidence

The most detailed recent liver experiment among the sources reviewed here is a 2022 study of saikosaponin d in metabolic-associated fatty liver disease (MAFLD), the condition formerly called non-alcoholic fatty liver disease.

• Model: mice fed a high-fat diet with glucose-fructose water, plus a human liver-cancer cell line (HepG2), mouse liver cells and fat cells in the dish.
• Result: saikosaponin d reduced fat build-up inside the liver and fat tissue of the mice.
• Mechanism: it acted like an activator of PPARα, a receptor that switches on fat burning, and that in turn raised INSIG proteins that block SREBP1c, a master switch for making new fat. When the researchers blocked PPARα with a drug, the effect disappeared.

A separate 2014 study tested four Japanese formulas, including shosaikoto, in genetically obese (db/db) mice fed a high-fat diet for six weeks. These mice developed liver changes resembling human non-alcoholic steatohepatitis. Shosaikoto lowered the liver enzyme ALT and reduced inflammation in the liver lobules compared with untreated high-fat-fed mice.

Neither study involved people. The site's Fatty Liver Disease page covers what has been tested in humans.

Fibrosis and Cirrhosis

Liver fibrosis is scarring laid down by activated cells in the liver (hepatic stellate cells) after repeated injury; advanced fibrosis becomes cirrhosis. A 2002 review of botanicals with anti-fibrotic properties stated that "animal studies indicate an antifibrotic potential of Shosaiko-to," a formula "frequently used in China and Japan for the treatment of chronic viral hepatitis," but that its mechanisms "need to be further explored." The same review noted a general lack of well-controlled human trials of anti-fibrotic botanicals, and that silymarin from milk thistle had not clearly shown an anti-fibrotic effect in human studies.

The 2018 saikosaponin review adds that the compounds have contradictory roles in liver fibrosis across studies. So the anti-fibrosis case for bupleurum rests on animals, and even there it is not consistent.

Hepatitis B: What the Trials Found

The largest body of human liver evidence is a 2010 systematic review of xiao chai hu tang for chronic hepatitis B, published in Chinese with an English abstract.

• What was included: 16 randomized trials with 1,601 patients, comparing the formula with placebo, with non-specific treatment, with antiviral drugs, or added to antivirals.
• Quality: one trial, published in English, was of good quality; the trials published in Chinese were of poor quality.
• Added to antivirals: the combination was more effective than antivirals alone at clearing hepatitis B markers from the blood and improving liver tests.
• Against placebo: xiao chai hu tang was not different from placebo in viral clearance or liver function.
• Against non-specific treatment: it did better on liver tests.
• Safety: the trials reported no adverse effects from the formula; adverse effects were reported with interferon.

The authors concluded that the formula "appears to be effective," but that because of the poor methodological quality of most trials, the potential benefits "need to be confirmed in rigorous clinical trials following international standards." Put plainly, where the comparison was fairest — against a dummy pill — there was no difference.

A 2013 review of traditional Chinese medicine for hepatitis B lists xiao chai hu tang, xiao yao san and saikosaponin among agents with anti-hepatitis B activity "in HepG2 2.2.15 cells, DHBV models, or patients." That sentence groups cell-culture, duck-virus model and patient evidence together, so it does not by itself show a benefit in people, and the review adds no new trial data. The site's Hepatitis B page covers established treatment.

Liver Cancer

A 2015 editorial asked whether herbal medicines reduce the risk of hepatocellular carcinoma (the main type of liver cancer). Its answer was that "whether herbal medicines can suppress the development of HCC remains to be established," and that clinical trials are warranted. Saikosaponin d's anti-tumour activity, reviewed in 2021, comes from cell and animal experiments. In one cell study, saikosaponin d made cultured bile-duct cancer cells more responsive to the chemotherapy drug gemcitabine when stress hormones were present. None of this is evidence in patients. See the Hepatocellular Carcinoma page for the condition itself.

The Other Side: Liver Injury Reports

The same root and formula appear in the literature on herb-induced liver injury:

• 2000 review, Public Health Nutrition: lists sho-saiko-to with Jin Bu Huan and Ma-Huang among Chinese herbal medicines with reported hepatotoxic effects. It notes that "many plant products do not seem to lead to toxic effects in everyone taking them" and often lack a strict dose relationship, and that for sho-saiko-to "the picture is confused further" by hepatoprotective properties of some components.
• 2014 review, Journal of Clinical and Translational Hepatology: lists chai hu, da chai hu tang ("major bupleurum decoction") and xiao chai hu tang among herbal products with potential hepatotoxicity, alongside others such as huang qin (skullcap) and gan cao (licorice). It notes that case quality was mixed, with problems including adulteration with synthetic drugs, heavy-metal contamination and misidentified plants.
• 2015 compilation, Annals of Hepatology: from 77 publications covering 57 herbs and mixtures, causality was established for 28 by the CIOMS liver-injury scale, a positive re-exposure (the injury returning when the herb was taken again), or both. Syo saiko to and xiao chai hu tang are both on that list of 28.
• 2006 case report, Taipei: acute hepatitis in a 52-year-old woman after six weeks of a xiao chai hu tang decoction, resolving two months after stopping (J Chin Med Assoc 2006).

The authors of the 2014 review concluded that a few herbal Chinese medicine products "may rarely be associated with hepatotoxicity in some susceptible individuals." These reports describe rare events; they do not give a rate. They do show that "liver herb" and "safe for the liver" are not the same claim.

Protection and Toxicity: A Dose Question

How can one compound protect the liver in one paper and injure it in another? The 2018 review points to the answer it says research has not yet supplied: the "dose-pharmacological/toxic relationship" of saikosaponins, and their metabolism. In animal and cell studies, researchers choose doses and routes (often injection) that may bear little relation to a decoction drunk by a person. The 2021 review notes that saikosaponin d can also alter the handling of other drugs through liver enzymes (CYPs) and the P-glycoprotein drug pump.

A 2023 review of the whole genus adds that "improper usage of Bupleurum may induce cytotoxic effects," and identifies polyacetylenes, a different chemical group, as possibly the main poisonous compounds. Some Bupleurum species are not the official medicinal ones, so species identity is part of the safety picture; the Chai Hu in Traditional Chinese Medicine page discusses species confusion.

Saikosaponins Beyond the Liver

For context, the same compounds have been tested in other organs, again almost entirely in animals and cells. A 2025 review of anti-inflammatory saponins includes saikosaponins alongside ginsenosides and glycyrrhizin. In mice with chemically induced colitis, saikosaponin a reduced gut inflammation and also lessened injury to the liver and spleen. In mice with surgically reduced kidney function, saikosaponins a and d reduced muscle wasting. A 2000 review reports that shosaikoto reduced atherosclerotic lesions in rabbits and mice without lowering blood lipids. These experiments show that saikosaponins are biologically active; they do not show benefit in people.

Where the Liver Evidence Stands

• Fatty liver: saikosaponin d and shosaikoto in mice; no human trial among the sources reviewed here.
• Fibrosis: animal studies only, with contradictory findings.
• Hepatitis B: formula trials mostly of poor quality; better with antivirals than antivirals alone; no different from placebo.
• Liver cancer: cell and animal work only.
• Liver injury: case reports and causality-assessed compilations for chai hu and the formula; dose- and accumulation-related toxicity of saikosaponins in reviews.

The research raises the most concern for people who already have liver disease, since they are the people the formula has traditionally been given to, and liver-injury reports are hardest to recognize against a background of existing liver problems. Questions about any herbal product alongside liver disease or its treatment are for a clinician.

What "Hepatoprotective" Usually Means in These Papers

"Hepatoprotective" sounds like a promise to patients. In most of the bupleurum literature it describes something narrower: in an animal or cell model, liver damage was first caused on purpose — for example with a high-fat diet, as in the mouse studies above — and the compound reduced markers of that damage, such as the liver enzyme ALT, fat droplets, or inflammation under the microscope.

Three gaps separate such a result from a benefit in people. The damage model may not resemble human disease. The dose and route in an experiment may not resemble what a person drinks in a decoction. And a lower liver enzyme is a laboratory marker, not the same as fewer people developing cirrhosis, liver cancer or liver failure. The 2018 saikosaponin review's call for study of the "dose-pharmacological/toxic relationship" and of saikosaponin metabolism points at exactly these gaps.

Terms Used on This Page

• ALT: a liver enzyme measured in the blood; it rises when liver cells are damaged.
• MAFLD / NAFLD / NASH: fatty liver disease linked to metabolism; NASH is the inflamed form.
• Fibrosis: scar tissue in the liver; advanced fibrosis is cirrhosis.
• Hepatic stellate cells: liver cells that lay down scar tissue when activated.
• PPARα and SREBP1c: switches inside cells that control fat burning and fat making.
• CIOMS scale: a standard scoring system used to judge whether a drug or herb caused a liver injury.
• Re-exposure (rechallenge): the injury returning when the suspect product is taken again, one of the strongest signs of causation.
• CYPs and P-glycoprotein: liver enzymes and a cell pump that handle many medicines; changes in them can raise or lower drug levels.

Key Research Papers

1. Li X, Li X, Huang N, et al. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2018;50:73-87. PubMed PMID: 30466994
2. Zhou P, Shi W, He XY, et al. Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics. Pharmaceutical biology. 2021;59(1):1480-1489. PubMed PMID: 34714209
3. Gu Y, Duan S, Ding M, et al. Saikosaponin D attenuates metabolic associated fatty liver disease by coordinately tuning PPARα and INSIG/SREBP1c pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2022;103:154219. PubMed PMID: 35691075
4. Takahashi Y, Soejima Y, Kumagai A, et al. Japanese herbal medicines shosaikoto, inchinkoto, and juzentaihoto inhibit high-fat diet-induced nonalcoholic steatohepatitis in db/db mice. Pathology international. 2014;64(10):490-8. PubMed PMID: 25229199
5. Stickel F, Brinkhaus B, Krähmer N, et al. Antifibrotic properties of botanicals in chronic liver disease. Hepato-gastroenterology. 2002;49(46):1102-8. PubMed PMID: 12143213
6. Qin XK, Li P, Han M, et al. [Xiaochaihu Tang for treatment of chronic hepatitis B: a systematic review of randomized trials]. Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2010;8(4):312-20. PubMed PMID: 20388470
7. Qi FH, Wang ZX, Cai PP, et al. Traditional Chinese medicine and related active compounds: a review of their role on hepatitis B virus infection. Drug discoveries & therapeutics. 2013;7(6):212-24. PubMed PMID: 24423652
8. Rino Y, Yukawa N, Yamamoto N. Does herbal medicine reduce the risk of hepatocellular carcinoma? World journal of gastroenterology. 2015;21(37):10598-603. PubMed PMID: 26457019
9. He H, Guo J, Hu Y, et al. Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling. Acta biochimica et biophysica Sinica. 2023;55(9):1404-1414. PubMed PMID: 37489008
10. Stickel F, Egerer G, Seitz HK. Hepatotoxicity of botanicals. Public health nutrition. 2000;3(2):113-24. PubMed PMID: 10948380
11. Teschke R. Traditional Chinese Medicine Induced Liver Injury. Journal of clinical and translational hepatology. 2014;2(2):80-94. PubMed PMID: 26357619
12. Teschke R, Zhang L, Long H, et al. Traditional Chinese Medicine and herbal hepatotoxicity: a tabular compilation of reported cases. Annals of hepatology. 2015;14(1):7-19. PubMed PMID: 25536637
13. Teng L, Guo X, Ma Y, et al. A comprehensive review on traditional and modern research of the genus Bupleurum (Bupleurum L., Apiaceae) in recent 10 years. Journal of ethnopharmacology. 2023;306:116129. PubMed PMID: 36638855
14. Ran S, Peng R, Guo Q, et al. Bupleurum in Treatment of Depression Disorder: A Comprehensive Review. Pharmaceuticals (Basel, Switzerland). 2024;17(4). PubMed PMID: 38675471
15. Zheng Q, Wang T, Wang S, et al. The anti-inflammatory effects of saponins from natural herbs. Pharmacology & therapeutics. 2025;269:108827. PubMed PMID: 40015518
16. Yang X, Yang J, Wang A, et al. Saikosaponin A ameliorates ulcerative colitis by targeting the CH25H/25-OHC axis to inhibit NLRP3 inflammasome in macrophages. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2025;143:156844. PubMed PMID: 40414048
17. Huang M, Yan Y, Deng Z, et al. Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2023;114:154766. PubMed PMID: 37002971
18. Inoue M. Shosaikoto as a potential antiatherosclerotic agent. Drug news & perspectives. 2000;13(7):407-12. PubMed PMID: 12937613

PubMed Topic Searches

1. PubMed: Saikosaponin and the liver
2. PubMed: Saikosaponin hepatotoxicity
3. PubMed: Xiaochaihu tang and hepatitis B
4. PubMed: Bupleurum and fatty liver

Connections

• Heart, Liver and Metabolic Herbs — the parent category
• Bupleurum (Chai Hu) — the main topic page
• Bupleurum Benefits Deep Dive — the hub
• Sho-Saiko-To and Interstitial Pneumonia
• Xiao Yao San and Mood Research
• Chai Hu in Traditional Chinese Medicine
• Milk Thistle — silymarin, the comparison in the fibrosis review
• Schisandra — another Chinese liver herb
• Dandelion — a traditional Western liver herb
• He Shou Wu: Liver Hepatotoxicity Warning — a parallel liver-injury story
• Fatty Liver Disease
• Cirrhosis
• Hepatitis B
• Hepatocellular Carcinoma