Current evidence for the hepatoprotective
activities of the medicinal mushroom
Patrick Ying-Kit Yue1*, Yi-Yi Wong1, Kay Yuen-Ki Wong1, Yeuk-Ki Tsoi2and Kelvin Sze-Yin Leung2*
Antrodia cinnamomea (AC) is an endemic mushroom species of Taiwan, and has been demonstrated to possess
diverse biological and pharmacological activities, such as anti-hypertension, anti-hyperlipidemia, anti-inflammation,
anti-oxidation, anti-tumor, and immunomodulation. This review focuses on the inhibitory effects of AC on hepatitis,
hepatocarcinoma, and alcohol-induced liver diseases (e.g., fatty liver, fibrosis). The relevant biochemical and molecular
mechanisms are addressed. Overall, this review summarizes the hepatoprotective activities in vitro and in vivo. However,
there is no doubt that human and clinical trials are still limited, and further studies are required for the development of
Antrodia cinnamomea (AC) (niu-chang-chih in Chinese)
is a medicinal mushroom (Figure 1) endemic to Taiwan.
It has been well-known for its medicinal properties, par-
ticularly with regard to liver complaints , since its first
identification as a new species by Zang and Su in 1990
. Among its diverse pharmacological activities, the
evidence for hepatic protection is the most recognized
and the strongest. Studies have shown that AC can in-
hibit hepatic tumor growth and retard the progression
of hepatitis [3,4]. Although AC is currently used as a
food supplement, the Food and Drug Administration
(FDA) has not approved any AC extracts or purified
compounds for clinical applications. Some AC products
are claimed to protect the liver against food and drug in-
toxication, especially alcohol-induced liver damage, main-
tain hepatic homeostasis, or both. This article reviews
the current evidence for the hepatoprotective proper-
ties (such as effects on hepatitis, cirrhosis, liver can-
cers, and alcoholic damage) of AC extracts and active
Effects on hepatitis
General background of hepatitis
Hepatitis is one of the top ten causes of death worldwide
(more than one million deaths per year), and is mainly
classified into hepatitis A, B, and C, involving different
types of viruses, epigenetic and genetic alterations, patho-
logical progressions, and clinical treatments . Hepatitis
A is an acute infectious liver disease caused by hepatitis A
virus (HAV). It is transmitted by a fecal-to-oral route, and
mainly occurs as outbreaks from fecal contamination of
food or water sources or direct contact with carriers. It
has no clinical signs or symptoms in most infected people,
and most cases recover within 1–2 months . Hepatitis
A causes the least problems among the various types of
hepatitis, and its incidence rate has been diminishing in
recent years, probably through improved hygiene .
Hepatitis B and C are acute and chronic infections caused
by hepatitis B virus (HBV) and hepatitis C virus (HCV),
respectively, and are more serious. HBV and HCV belong
to the Hepadnaviridae and Flaviviridae, respectively. HBV
is a DNA virus that can integrate into the host genome
after infection, while HCV is an RNA virus that has no
such ability . According to a worldwide epidemiological
evaluation, at least 400 and 170 million people are chron-
ically infected with HBV and HCV, respectively [7,8]. In
fact, these viruses persist in the liver in about 80% of in-
fected people , and such chronic viral infections may be
* Correspondence: firstname.lastname@example.org; email@example.com
1Department of Biology, Faculty of Science, Hong Kong Baptist University,
Hong Kong, SAR, China
2Department of Chemistry, Faculty of Science, Hong Kong Baptist University,
Kowloon, Hong Kong SAR, China
© 2013 Yue et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Yue et al. Chinese Medicine 2013, 8:21
associated with chronic inflammation that leads to scar-
ring of the liver tissues and cirrhosis . Upon infection,
HBV and HCV interact with host hepatocytes, impair cell
metabolism (e.g., induce cell death) , modulate signal-
ing pathways of protein synthesis (e.g., produce viral pro-
teins and enzymes) [12,13] and immunity (e.g., synthesize
and place viral antigens on host cell surfaces) , and de-
velop immortalization (e.g., modulate surface markers).
Ultimately, 1–5% of cirrhotic livers develop hepatocellular
carcinoma (HCC) .
Inhibition of viral proteases, which are crucial for viral rep-
lication, can interrupt viral protein maturation. Antrodins
(A to E) and their metabolic analogues selectively inhibited
HCV NS3/4A protease activity . Among these, antrodin
A (the major in vivo metabolite of antrodin C) showed the
highest potency with an IC50of 0.9 μg/mL, while antrodin
B showed lower potency with an IC50of >100 μg/mL.
Moreover, polysaccharides isolated from fruiting bodies
and cultured mycelia of AC inhibited HBV replication
activity . After an HBV-producing cell line (MS-G2)
was treated with the AC-extracted polysaccharides, anti-
hepatitis B surface antigen (HBsAg) and anti-hepatitis B e
antigen (HBeAg) were reduced . Moreover, the AC-
extracted polysaccharides (50 μg/mL) were found to be
more effective than interferon-α (IFN-α) (1000 U/mL) for
HBsAg and HBeAg inhibition . Huang et al. 
showed that 2,2′,5,5′-tetramethoxy-3,4,3′,4′-bis(methly-
lene-dioxy)-6,6′-dimethylbiphenyl (50 μM) could suppress
the HBsAg and HBeAg levels in a wild-type HBV-
producing cell line (ES2) within a non-toxic range and
in a dose-dependent manner. These findings indicate that
AC can effectively attenuate hepatitis virus-induced dam-
age by inhibiting essential viral enzyme activities and anti-
Effects on HCC
Pathogenesis of HCC
Liver cancer comprises diverse hepatic neoplasms, in-
cluding HCC, cholangiocarcinoma, hepatoblastoma, and
hemangiosarcoma [18,19]. Among these, HCC is the pri-
mary malignant hepatic cancer worldwide, the fifth most
common cancer, and the third leading cause of cancer
death around the world [20-22]. The incidence and mor-
tality of HCC are both increasing [23-26]. HCC arises in
the context of chronic viral hepatitis (e.g., HBV, HCV,
and HDV infection), cirrhosis, alcoholism, toxin or drug
poisoning (e.g., aflatoxins), and metabolic disorders (e.g.,
diabetes, non-alcoholic fatty liver disease, and hereditary
diseases) . Recently, geographical differences in HCC
incidence have been related to the changing distribution
and natural history of HBV and HCV infections .
The World Health Organization (WHO) reported that
HBV is a human carcinogen, and that an estimated 300–
400 million individuals are chronically infected with
HBV worldwide . Moreover, a large number of car-
riers fail to eliminate the virus, and progress to chronic
viral infection. Continuous hepatic inflammation can lead
to chronic hepatitis and cirrhosis. The incidence of HCC
in chronically HBV-infected or cirrhotic individuals is
100- and 1000-fold higher, respectively, than in uninfected
individuals [27,30]. For toxin-induced HCC, ingestion of
aflatoxin-B1 (a fungal toxin classified as a type I carcino-
gen by the International Agency for Research on Cancer
(IARC) and produced by the molds Aspergillus flavus and
Figure 1 Morphological appearance of Antrodia cinnamomea.
Yue et al. Chinese Medicine 2013, 8:21
Page 2 of 7
Aspergillus parasiticus found in contaminated food) in-
creased the risk of HCC development [31,32]. Aflatoxin-
B1 also induced mutations in codon 249 of the p53 tumor
suppressor gene and the RAS oncogene [33-36]. Alcohol,
which is also classified as a type I carcinogen, is another
critical HCC risk factor [31,32]. Alcohol activates mono-
cytes and induces pro-inflammatory cytokine produc-
tion, and the subsequent increase in endotoxins activates
Kupffer cells to release chemokines and cytokines (e.g.,
tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and
interleukin-6 (IL-6)). The resulting oxidative stress acti-
vates stellate cells to synthesize large amounts of collagen,
leading to fibrosis, cirrhosis, and ultimately HCC [37-39].
Apart from these etiological agents, inflammation, oxida-
tive stress, genetic alternations, activation of oncogenes,
inactivation of tumor suppressor genes, genomic instabil-
ity, and overexpression of growth and angiogenic factors
are related to the pathogenesis of HCC [31,40].
Angiogenesis plays an important role in the pathogen-
esis (i.e., tumor growth, invasion, and metastasis) of all
types of solid tumors, including HCC . As a hyper-
vascular tumor, HCC develops and progresses from a
small, avascular, and well-differentiated HCC to a large,
highly vascular, and poorly differentiated HCC within a
short period . The expanded endothelium provides a
channel for HCC cells to enter the blood circulation sys-
tem and metastasize to different tissues. During tumor
angiogenesis, angiogenic factors (e.g., vascular endothe-
lial cell growth factor (VEGF), fibroblast growth factor-2
(FGF-2), angiogenin, or angiopoietins) and their recep-
tors are produced by tumor cells and endothelial cells
(ECs) [43,44]. ThroughVEGF signaling, the most common
and potent angiogenic signaling pathway, ECs express
VEGF receptors (VEGFR-1 and -2), receive signals from
tumor-generated VEGF, proliferate, migrate toward tumor
tissues, and form functional neovessels [43,44]. Moreover,
these angiogenic factors induce gene transcriptional, bio-
chemical, and enzymatic activities, such as extracellular
digestion of extracellular matrix by matrix metalloprotein-
ases (MMPs), cell cycle progression, and production of
bioactive molecules (e.g., angiogenic factors, cytokines,
and chemokines) [43,44]. As a result, both tumor cells and
ECs are activated in a feedback mechanism, thereby facili-
tating tumorigenesis .
Various types of AC extracts and purified components
(e.g., antcin A, B, and C, antroquinonol, methyl antcinate
A (MAA), methyl antcinate B (MAB) ethylacetate, and
methanolic, ethanolic and fermented extracts) exhibit cy-
totoxicity through apoptosis in various cancers, especially
hepatic carcinoma. Apoptosis is processed sequentially
through the activation of death receptors (e.g., Fas re-
ceptor) and downstream caspases (e.g., caspase-3, -8,
and -9), and mitochondrial function disruption. MAA
(30.2–78 μM) and antcins A and C (30.2–286.4 μM)
stimulate a series of apoptotic pathway cascades, in-
cluding caspase-2, -3, and -9 activation, Bax, Bak, and
PUMA protein expression, Bcl-(XL) and Bcl-2 suppres-
sion, and cytochrome c release, resulting in apoptosis
[46-48]. MAB and antcin B (100 μM)-induced apop-
tosis is characterized by increased DNA fragmentation,
cleavage of PARP, sub-G1 population appearance, and
chromatin condensation . Moreover, AC components
induced NADPH oxidase-provoked oxidative stress [49,50].
Another purified AC component, antroquinonol, inhibited
HepG2 (IC50: 0.13 μM) and Hep3B (IC50: 4.3 μM) cell
growth [50,51]. Recently, Chiang et al.  demonstrated
that antroquinonol induced HCC apoptosis through AMPK
activation and mTOR translational pathway inhibition, and
induced cell cycle arrest through downregulation and sup-
pressed nuclear translocation of cyclin D1, cyclin E, Cdk4,
and Cdk2. An AC ethyl acetate extract (IC50: 42.5 μg/mL in
HepG2 cells; 78.3 μg/mL in Hep3B cells), methanolic ex-
tract (IC50: 49.5 μg/mL in HepG2 cells; 62.7 μg/mL in
Hep3B cells), and ethanolic extract (IC50: 54.2 μg/mL in
HepG2 cells; 82.9 μg/mL in Hep3B cells) could also inhibit
growth in a similar manner [4,46,48,53,54]. Apart from the
direct cytotoxicity, cell cycle arrest can be used for control-
ling tumor growth. During the G1 phase of the cell cycle,
the cells increase in size and synthesize essential proteins
for the resting steps of the cell division process. It is import-
ant to control whether a cell goes into the S phase (DNA
synthesis phase) or escapes from the cell cycle. An AC my-
celium extract, 4-acetylantroquinonol B (EC50: 0.1 μg/ mL),
induced cell cycle arrest in HepG2 cells, indicating that
cells were unable to divide. Western blotting analyses
further showed that the protein expressions of different
cell cycle-regulating proteins, CDK2 and CDK4, were de-
creased, while p21, p27, and p53 were increased in HepG2
cells after the AC treatment [55,56]. Similar to the case for
the conventional anti-cancer drug cisplatin, tumor cell pro-
liferation can be inhibited through induction of DNA dam-
age, cell cycle arrest, and apoptosis. This suppresses the size
of tumor tissues, and reduces the chance for subsequent
Anti-angiogenic therapy has been explored as a thera-
peutic approach to HCC [59,60]. A series of angiogenic
inhibitors, e.g., bevacizumab (for blocking the angiogenic
factor VEGF), endostatin, IFN-α, cyclooxygenase-2 (for
inhibiting EC migration, tube formation, proliferation,
and angiogenic factor production), interleukin-12 (for
producing anti-angiogenic factors), and erlotinib and ge-
fitinib (for inhibiting epidermal growth factor receptor
tyrosine kinase activation) are currently in different phases
of clinical trials .
An AC ethyl acetate extract and AC polysaccharides in-
hibited angiogenesis in vitro and in vivo. The ethyl acetate
Yue et al. Chinese Medicine 2013, 8:21
Page 3 of 7
extract was shown to inhibit cancer invasion of human liver
cancer PLC/PRF/5 cells through suppression of angiogenic
factor (e.g. VEGF) and extracellular digestive enzyme (e.g.
MMP-2 and -9) production, and elevation of enzyme in-
hibitor (tissue inhibitor of metalloproteinases (TIMP)-1 and
TIMP-2) production in the concentration ranges of 10 to
40 μg/mL . These results were confirmed in an animal
model by Matrigel plug angiogenesis assays, in which the
ethyl acetate extract (300 mg/kg) significantly suppressed
tumor growth in nude mice . The VGEF-induced tube
formation and migration of ECs, and neovessel formation
on chorioallantoic membranes were effectively inhibited
by the AC polysaccharide extract [62,63]. Cheng et al.
 demonstrated that the different fractionated AC
polysaccharide extracts were able to inhibit VEGF pro-
tein expression, binding of VEGF to VEGFR-2, and
VEGFR-2 phosphorylation, suggesting that inhibition of
VEGF interactions with VEGF receptors is an anti-
angiogenic mechanism of AC.
Anti-angiogenic therapy is particularly promising, be-
cause it is expected to minimize the devastating side effects,
such as hair loss, bleeding, and immunosuppression, that
are commonly associated with conventional chemotherapy.
We previously found that many herbal medicines and
natural compounds, such as ginsenosides, indirubin deriva-
tives, and sinomenine, possess anti-angiogenic activities
[65-70]. Therefore, AC may also contain anti-angiogenic
Effects on alcohol metabolism
Metabolism of alcohol and its related diseases
Chronic excessive consumption of alcohol often causes
serious health problems, especially to the liver, such as
cirrhosis and HCC [18,71]. According to the WHO, al-
cohol is the third largest risk factor for disease world-
wide, and has been classified as a type I carcinogen by
the IARC . It has been estimated that alcohol leads
to 2.5 million deaths each year, and that 320,000 of these
deaths are in the age group of 15–29 years, representing
9% of all deaths in that age group . Alcohol, a water-
soluble small molecule, is easily absorbed into the blood-
stream from the gastrointestinal tract. It cannot be stored,
and is either metabolized or excreted [74,75]. More than
90% of absorbed alcohol is oxidized by hepatocytes, while
the remainder is excreted through pulmonary respiration
and urinary excretion [75,76]. There are three major path-
ways for metabolizing alcohol. The primary pathway of
alcohol metabolism is the alcohol dehydrogenase (ADH)-
mediated ethanol oxidation pathway [76,77]. ADH com-
prises a group of cytosolic enzymes that convert alcohol
to acetaldehyde utilizing NAD+as a coenzyme, and the el-
ements of this pathway are mainly located in the liver. At
high alcohol concentrations (above 100 mg/dL) or during
chronic alcohol consumption, the ADH pathway may
become saturated through NAD+depletion. When this
happens, the secondary pathway, the microsomal ethanol
oxidizing system, is used to break down alcohol [76,77]. In
this system, cytochrome P450 enzymes such as CYP2E1,
CYP1A2, and CYP2A4 metabolize alcohol to acetaldehyde
via NADPH as a coenzyme instead of NAD+[76,78]. The
third pathway is the hydrogen peroxide (H2O2)-generating
system in peroxisomes , which oxidizes alcohol to
acetaldehyde and water molecules [75,77]. The acetalde-
hyde product is further oxidized by aldehyde dehydrogen-
ase (ALDH) to acetate, and subsequently processed in the
citric acid cycle. The final products are carbon dioxide,
water, and ATP. Through the ADH and ALDH-mediated
reactions, NAD+is used up in the form of a coenzyme,
and NADH is generated. This increased ratio of NADH:
NAD+redox potential in the liver inhibits mitochondrial
β-oxidation of fatty acids and reduces lipid expenditure,
resulting in lipogenesis and lipid accumulation in hepato-
cytes [79,80]. The severity of this alcoholic liver disease
(ALD) depends on the amount, frequency, and duration
of alcohol consumption, and can further develop into more
complicated liver damage states, including fibrosis, steato-
hepatitis, cirrhosis, and cancer [81-83].
Different types of AC preparations, including ethanolic
extracts, aqueous extracts, fermented filtrates, and crude
powder, can protect the liver against alcohol damage.
Ethanol-induced ALD rats were orally treated with AC
ethanolic extracts at a range of 0.25–1.25 g/kg. Hepatic
damage was assessed using serum markers of liver dam-
age, including aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase (ALP)
. When liver cells are damaged, these enzymes are
released into the bloodstream where they can be detected
with biochemical or immunological assay kits. The AC ex-
tracts could prevent ethanol- and carbon tetrachloride
(CCl4)-induced elevations of the AST, ALT, and ALP levels
in the rat blood serum [85,86], indicating that AC con-
ferred protection against chemical-induced liver damage.
Moreover, the AC ethanolic extract could normalize
the alcohol-induced increase in malondialdehyde, and de-
creases in glutathione peroxidase, reductase, and glutathi-
one levels in the liver [86,87]. In the CCl4-induced ALD
model, AC extracts could restore the reduction in the hep-
atic glutathione content and catalase (CAT) activity, and
prevent free radical formation and lipid peroxidation .
These in vivo data were validated in a HepG2 cellular
model by Kumar et al. , who showed that the antroqui-
nonol from the AC ethanolic extract could protect ethanol-
induced HepG2 cells against heme oxygenase 1, NF-E2
released factor (Nrf-2), and mitogen-activated protein kin-
ase activation (MAPK).
Yue et al. Chinese Medicine 2013, 8:21
Page 4 of 7
An AC fermented filtrate protected HepG2 cells against
damage caused by CCl4 and H2O2. Song et al. 
demonstrated that the AC fermented filtrate (0.05–0.5 mg/
mL) suppressed lipid peroxidation in H2O2-induced HepG2
cells. The AC fermented filtrate restored the CCl4-induced
increases in ALT, AST, lipid peroxidation, liver lesions, neu-
trophil infiltration, hydropic swelling, and necrosis, and the
reductions in glutathione peroxidase, reductase, and
transferase in animal tests . The liver damage
caused by chronic alcohol consumption was found to
be reduced by an AC crude powder. Chen et al. 
demonstrated that AC crude powder-treated rats had rela-
tively smaller livers, less lipid accumulation, and lower AST,
ALP, and serum alcohol levels. In addition, their serum and
hepatic MMP-9 activities, and TNF-α, krueppel-like factor-
6 (KLF-6), and transformation growth factor-β (TGF-β)
gene expressions were downregulated. Moreover, the AC
powder could enhance the metabolism of alcohol by in-
creasing the CATand ALDH activities . Chen et al. 
further demonstrated that the AC crude powder induced
downregulation of 3-hydroxy-3-methylglutaryl-CoA reduc-
tase, sterol regulatory element-binding protein-1c, acetyl-
CoA carboxylase, fatty acid synthase, and malic gene
expression, and upregulation of low-density lipoprotein
receptor and peroxisome proliferator-activated alpha gene
expression . A dried powder from fermented AC
mycelium (0.34–0.57 g/kg) could protect the rat liver
against damage from alcohol, and significantly suppress
the alcohol-induced increases in glutamate-pyruvate
aminotransferase, glutamate-oxaloacetate aminotrans-
ferase, superoxide dismutase, and CAT activities. Histo-
logical data validated the AC protective effects by showing
a reduction in alcohol-induced lipid vacuole accumulation,
and hydropic degradation of hepatocytes .
Hepatoprotective activities, including anti-hepatitis, anti-
hepatocarcinoma, and anti-alcoholism, of AC have been
demonstrated in vitro and in vivo. However, many of the
underlying mechanistic actions, such as the pharmaco-
kinetics and pharmacodynamics, remain unclear. Fur-
thermore, human and clinical trials are required for a
full evaluation of this valuable medicinal mushroom for
potential clinical applications.
AC: Antrodia cinnamomea; FDA: Food and Drug Administration;
HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus;
HDV: Hepatitis D virus; HCC: Hepatocellular carcinoma; HBsAg: Hepatitis B
surface antigen; HBeAg: Hepatitis B e antigen; IFN-α: Interferon-α;
WHO: World Health Organization; IARC: International Agency for Research on
Cancer; TNF-α: Tumor necrosis factor; IL-1β: Interleukin-1β; IL-6: Interleukin-6;
VEGF: Vascular endothelial cell growth factor; FGF-2: Fibroblast growth
factor-2; EC: Endothelial cell; VEGFR-1: VEGF receptor 1; VEGFR-2: VEGF
receptor 2; MMP: Matrix metalloproteinase; MAA: Methyl antcinate A;
MAB: Methyl antcinate B; TIMP-1: Tissue inhibitor of metalloproteinases-1;
TIMP-2: Tissue inhibitor of metalloproteinases-2; ADH: Alcohol
dehydrogenase; H2O2: Hydrogen peroxide; ALDH: Aldehyde dehydrogenase;
ALD: Alcoholic liver disease; AST: Aspartate aminotransferase; ALT: Alanine
aminotransferase; ALP: Alkaline phosphatase; CCl4: Carbon tetrachloride;
CAT: Catalase; Nrf-2: NF-E2 released factor; MAPK: Mitogen-activated protein
kinase activation; ALDH: Aldehyde dehydrogenase.
The authors declare that they have no competing interest.
PYKY was responsible for drafting and proofreading of this article. The
information searching was done by YYW, KYKW, and YKT. Final proofreading
was done by KSYL. All authors read and approved the final manuscript.
K.S.Y. Leung would like to thank the Hong Kong Baptist University for
financial support. The generous support of GeneFerm Biotechnology
Company Limited of Taiwan for the entire research on Antrodia cinnamomea
is gratefully acknowledged.
Received: 8 May 2013 Accepted: 23 October 2013
Published: 1 November 2013
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Cite this article as: Yue et al.: Current evidence for the hepatoprotective
activities of the medicinal mushroom Antrodia cinnamomea. Chinese
Medicine 2013 8:21.
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