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\DOI{10.5802/crchim.411}
\datereceived{2025-04-22}
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\dateposted{2025-10-02}
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\CDRsetmeta{articletype}{review}

\title{Major phytoconstituents of \protect\textit{temulawak}
(\protect\textit{Curcuma xanthorrhiza}) in hepatoprotective activity}

\alttitle{Principaux phytoconstituants du \protect\textit{temulawak}
(\protect\textit{Curcuma xanthorrhiza}) et activit\'{e}
h\'{e}patoprotectrice}

\author{\firstname{Jumardi} \lastname{Jumardi}\IsCorresp}
\address{Asy-Syatiby School, Gowa, South Sulawesi, 92119, Indonesia}
\email[J. Jumardi]{jumardimukhl@gmail.com}

\author{\firstname{Mohammad} \lastname{Wijaya}\CDRorcid{0000-0002-5770-7061}}
\address{Department of Chemistry, State University of Makassar, 90222, Indonesia}

\keywords{\kwd{\textit{C. xanthorrhiza}}
\kwd{Curcuminoid}
\kwd{Liver disease}
\kwd{\textit{Temulawak}}
\kwd{Xanthorrhizol}}

\altkeywords{\kwd{\textit{C. xanthorrhiza}}
\kwd{Curcumino\"{i}de}
\kwd{Maladie h\'{e}patique}
\kwd{\textit{Temulawak}}
\kwd{Xanthorrhizol}}

\begin{abstract}
\textit{C. xanthorrhiza}, commonly known as Javanese turmeric or
\textit{temulawak} in Indonesia, belongs to the Zingiberaceae family.
\textit{C. xanthorrhiza} is widely used to treat various health
problems, including loss of appetite, gastrointestinal disorders,
constipation, diarrhea, fever, arthritis, and liver dysfunction.  In
Indonesia,  \textit{C. xanthorrhiza} is widely recognized and
traditionally used for liver disease treatment, although its
hepatoprotective mechanisms were not scientifically validated in
traditional practice. Current research has identified xanthorrhizol and
curcuminoids (including curcumin and bisdemethoxycurcumin) as the
primary active compounds in  \textit{C. xanthorrhiza}, which exert
hepatoprotective effects through various studied mechanisms.
\end{abstract}

\begin{altabstract}
\textit{C. xanthorrhiza}, commun\'{e}ment appel\'{e} curcuma javanais
ou \textit{temulawak} en Indon\'{e}sie, appartient \`{a} la famille des
zingib\'{e}rac\'{e}es. \textit{C. xanthorrhiza} est largement
utilis\'{e} pour traiter divers probl\`{e}mes de sant\'{e}, notamment
la perte d'app\'{e}tit, les troubles gastro-intestinaux, la
constipation, la diarrh\'{e}e, la fi\`{e}vre, l'arthrite et les
dysfonctionnements h\'{e}patiques. En Indon\'{e}sie, \textit{C.
xanthorrhiza} est largement reconnu et traditionnellement utilis\'{e}
pour le traitement des maladies du foie, bien que ses m\'{e}canismes
h\'{e}patoprotecteurs n'aient pas \'{e}t\'{e} scientifiquement
valid\'{e}s dans la m\'{e}decine traditionnelle. Les recherches
actuelles ont identifi\'{e} le xanthorrhizol et les curcumino\"{i}des
(y compris la curcumine et la bisd\'{e}m\'{e}thoxycurcumine) comme les
principaux compos\'{e}s actifs de \textit{C. xanthorrhiza}, qui
exercent des effets h\'{e}patoprotecteurs par le biais de divers
m\'{e}canismes \'{e}tudi\'{e}s.
\end{altabstract}

 \maketitle

\twocolumngrid

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\section{Introduction}\label{sec1}
Chronic liver disease has emerged as a leading cause of mortality,
particularly in developing countries. Recent years have witnessed a
significant increase in its prevalence. In developed nations, the
majority of chronic liver diseases comprise alcoholic liver disease,
chronic viral hepatitis (including hepatitis B and C), non-alcoholic
fatty liver disease (NAFLD), and  hemochromatosis~\cite{1,2}.

Multiple signaling pathways that contribute to tumor development have
been identified, presenting opportunities for targeted therapies that
can specifically target the components involved in 
carcinogenesis~\cite{3,4}. In conventional medicine, surgical
resection, liver transplantation, radiofrequency, chemotherapy, and 
targeted molecular therapy are the primary approaches used to treat
liver  cancer~\cite{5}. However, recurrence of the disease and drug
toxicity or ineffectiveness, which can adversely affect the \mbox{patient's}
quality of life after therapy, remain major challenges. Chemotherapy,
for example, is often associated with severe side effects that can
interfere with treatment. Although sorafenib was generally
well-tolerated, toxicities were mild to moderate in severity and
included hypertension, hemorrhage, neuropathy, leukopenia, lymphopenia,
diarrhea, nausea, vomiting, and  dyspnea~\cite{6,7}. Furthermore,
repeated use of transarterial chemoembolization (TACE) has been linked
to fibrosis, toxicity, and hypofunction of the  liver~\cite{8}.

In Indonesia, \textit{Curcuma xanthorrhiza} is commonly used in
traditional medicine for liver disease treatment. This herbal practice
has been passed down through generations, with its application based
primarily on empirical evidence of therapeutic effects rather than
specific knowledge of its pharmacological mechanisms. 
\textit{C.~xanthorrhiza}, commonly known as Javanese turmeric or
\textit{temulawak} in Indonesia, belongs to the Zingiberaceae 
family~\cite{9}. It is found both in the wild and under cultivation
throughout Indonesia and has long been used in traditional medicine. In
addition to its medicinal applications, \mbox{\textit{C.~xanthorrhiza}} is
also commonly consumed as a health  tonic~\cite{10}.

Although \textit{C.~xanthorrhiza} belongs to the same family as
turmeric (\textit{C.~longa}), it is not as widely known or used outside
of Indonesia. The two species exhibit notable differences in rhizome
characteristics, including size, color, and odor. The rhizomes of
\textit{C.~xanthorrhiza} are typically larger than those of 
\textit{C.~longa}. In terms of coloration, \textit{C.~longa} exhibits a
brighter and more intense yellow--orange hue, while
\textit{C.~xanthorrhiza} tends to have a duller color. Regarding aroma,
\textit{C.~xanthorrhiza} possesses a more pungent and distinctive odor
compared to \textit{C.~longa}.

Due to these differences, particularly in odor and color, 
\textit{C.~xanthorrhiza} is predominantly used for medicinal purposes,
such as in traditional herbal formulations (\textit{jamu}), rather than
in culinary applications. In contrast, \textit{C.~longa} is widely used
both as a medicinal ingredient and a culinary spice. The strong and
distinctive smell of \textit{C.~xanthorrhiza} is considered to reduce
the sensory appeal of food, limiting its use in cooking.

\textit{C. xanthorrhiza} is widely used to treat various health
conditions, including loss of appetite, gastrointestinal disorders,
constipation, diarrhea, fever, arthritis, and liver dysfunction.
Compared to \textit{C.~longa}, \textit{C.~xanthorrhiza} is more
frequently utilized in herbal products and traditional medicines as a
source of curcumin. Several studies have reported a range of biological
activities associated with \textit{C.~xanthorrhiza}, including
antimicrobial, antibacterial, antinociceptive, antioxidant, anticancer,
and anti-inflammatory  effects~\cite{11,12}. These pharmacological
properties are largely attributed to its major bioactive constituents,
particularly curcuminoids and xanthorrhizol. Curcuminoids, which belong
to the diarylheptanoid class of compounds, include curcumin,
demethoxycurcumin, and bisdemethoxycurcumin, each of which is present
in  \textit{C.~xanthorrhiza}~\cite{13}.

\textit{C.~xanthorrhiza} is a medicinal plant that plays a significant
role in promoting health. However, despite belonging to the same family
as \textit{C.~longa}, the two species are not closely related in terms
of phytochemical composition and usage. Scientific publications
specifically focused on \textit{C.~xanthorrhiza} remain limited across
major academic databases. Given the scarcity of existing literature,
this review aims to provide a comprehensive overview of 
\mbox{\textit{C.~xanthorrhiza}}, with an emphasis on its distribution,
cultivation practices, botanical characteristics, nutritional
composition, phytochemistry, traditional and medicinal uses, as well as
its pharmacological activities and safety profile.

\section{Botanical description, geographical\newline 
distribution, and cultivation of\newline  
\textit{C.~xanthorrhiza} Roxb.}\label{sec2}  
\textit{C.~xanthorrhiza} is a plant native of Indonesia and is commonly
found growing wild in forested areas, particularly under the shade of
teak trees. It is widely distributed across several Indonesian islands,
including Java, Maluku, and Kalimantan, and is also found in other
Southeast Asian countries, as well as in India and  China~\cite{14}.
Taxonomically, \textit{C.~xanthorrhiza} belongs to the  kingdom
Plantae, division Magnoliophyta, class Liliopsida, order Zingiberales,
family Zingiberaceae, and  genus \textit{Curcuma}, with the species
designation \textit{Curcuma xanthorrhiza} Roxb~\cite{15,16}. The
taxonomic classification of \textit{C.~xanthorrhiza} is shown in 
Figure~\ref{fig1}. 

\begin{figure*}
\includegraphics{fig01}
\vspace*{-1pt}
\caption{\label{fig1}The taxonomic classification and important parts
of \textit{C.~xanthorrhiza}.}
\vspace*{-3pt}
\end{figure*}

\textit{C.~xanthorrhiza} is a perennial herbaceous plant that grows in
clumps, with each clump consisting of several shoots. Each shoot
typically bears two to nine leaves. The leaves are oval, elongated, or
lanceolate in shape, and range in color from green to light or dark
purplish brown, often marked with brown stripes. They measure
approximately 31--84~cm in length and 10--18~cm in width. The leaves
are complete, consisting of a leaf sheath, petiole, and leaf blade. The
plant features a pseudostem, from which flowers emerge once the plant
reaches maturity, typically at a height of up to 2.5~m. The flowers are
relatively short and broad, displaying a white coloration with reddish 
hues~\cite{17,18}.

The main rhizome of \textit{C.~xanthorrhiza} is generally round and
egg-shaped, with a relatively large size. Elongated lateral rhizome
branches grow from the sides of the main rhizome, typically numbering
three to four per plant. These lateral branches are usually younger and
lighter in color compared to the parent rhizome. The outer skin of both
young and mature rhizomes ranges from dirty yellow to reddish brown.
The inner flesh of the rhizome is yellow to deep orange, characterized
by a bitter taste and a distinctive, sharp aroma with moderate 
fragrance~\cite{18}. Rhizomes develop underground at an approximate
depth of 16~cm. On average, each ginger clump consists of around six
mature rhizomes and five younger ones.

Propagation of \textit{C.~xanthorrhiza} is typically carried out using
rhizome cuttings, either from the main rhizome or from lateral
branches. Planting material should be selected from healthy plants aged
ten to twelve months, with clean, smooth, shiny skin, and free from
pests and diseases. The parent rhizome can be divided into two to four
segments, each weighing approximately 20--40~g and containing
two--three viable buds. \textit{C.~xanthorrhiza} is usually ready for
harvest at around ten to twelve months of age. The optimal harvest time
is indicated by plant senescence, marked by the drying of stems and
leaves.

\section{Traditional/ethnomedicinal uses of\newline \textit{C.~xanthorrhiza}
Roxb.}\label{sec3} 
\textit{C.~xanthorrhiza} has long been utilized by the Indonesian
population for various purposes, including as food coloring agent,
culinary ingredient, and medicinal remedy. It is commonly used in the
preparation of traditional Indonesian herbal drinks, known as
\textit{Jamu}, which typically include tamarind, kencur, pandan leaves,
and a small amount of palm sugar as a sweetener. In traditional
medicine, \textit{C.~xanthorrhiza} is valued for its ability to enhance
endurance and stamina, as well as for its beneficial effects on
digestive  health~\cite{16,19}. It is used to alleviate stomach-related
conditions, such as gastritis (inflammation of the stomach lining),
promote the healing of gastric ulcers, prevent stomach cancer,
neutralize excess stomach acid, and combat stomach infections.
Additionally, \textit{C.~xanthorrhiza} is believed to help relieve
various digestive complaints, including constipation, nausea, bloating,
vomiting, heartburn, and loss of  appetite~\cite{20,21}.

Some medicinal products contain \textit{C.~xanthorrhiza} such as
Curcuma Plus (PT SOHO Industri Pharmasi, Indonesia), Curcuma (PT SOHO
Industri Pharmasi, Indonesia), Sari Temulawak (Sidomuncul), Herbadrink
Sari Temulawak, Curcuma Sanbe (Sanbe Farma), and several other
products. Generally, these products have  the properties to help
maintain healthy liver function and help improve appetite.

The Traditional Herbal Medicine Formulary from the Indonesian Ministry
of Health provides guidelines for the proper consumption of 
\textit{C.~xanthorrhiza}. To prepare fresh \textit{temulawak}, 25--50~g
of the rhizome is heated in water until it reaches a boil. The
resulting boiled water should be consumed 1~h before eating.
Alternatively, \textit{temulawak} can be dried and ground into a
powder. A recommended dose is 5--15~g of the powdered rhizome, which
should be brewed with hot water and consumed while  warm~\cite{22}.

A case study involving Dr Melly Budiman highlights the potential
benefits of \textit{temulawak} for liver health. Dr.~Melly, who had been
diagnosed with liver problems that she suspected were caused by needle
transmission, was initially prescribed a high dose of corticosteroids
(4 ${\times}$ 10~mg) by her treating physician. However, the treatment
was ineffective and resulted in significant side effects, including
body swelling. Eventually, Dr.~Budiman decided to try consuming boiled
\textit{temulawak} water daily for four consecutive months. Upon
subsequent biopsy analysis by Dr.~Sadikin Darmawan, a senior
pathologist, the results indicated that Dr Budiman's liver condition
had returned to a healthy state.

\section{Phytochemistry}\label{sec4}
Among the chemicals present in \textit{C.~xanthorrhiza}, curcuminoids
and terpenoids are the majority, and they possess essential biological
properties. The major chemical constituents of \textit{C.~xanthorrhiza}
are shown in  Figure~\ref{fig2}.

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}Chemical structures of terpenoids present in
\textit{C.~xanthorrhiza}.}
\end{figure*}

\subsection{{Terpenoids} (see  Figure~\myRef{fig2} for chemical\newline
structures)}
Various studies have shown that \textit{C.~xanthorrhiza} contains a
variety of terpenoids. Septama  et~al.\ reported the results of a GC-MS
analysis of essential oil extracted from \textit{C.~xanthorrhiza},
identifying 42 compounds, primarily consisting of sesquiterpene
hydrocarbons (13 compounds):   $\updelta$-elemene, $\upalpha$-cubebene,
copaene, 7-episesquithujene, sesquithujene,
\textit{cis}-$\upalpha$-bergamotene, caryophyllene, 
$\upgamma$-elemene, $\upbeta$-farnesene, $\upalpha$-curcumene,
$\upbeta$-curcumene,
\mbox{$\upbeta$-sesquiphellandrene,} germacrene b;
oxygenated sesquiterpenes (8 compounds): curzerene,
\textit{cis}-sesquisabinene hydrate, $\upbeta$-elemenone,
isospathuleno, $\upbeta$-bisabolol, germacrone, curcuphenol,
xanthorrhizol; oxygenated monoterpenes (8 compounds): 
eucalyptol/1,8-cineole, sabinene hydrate, linalool, camphor,
isoborneol, borneol, terpinen-4-ol, $\upalpha$-terpineol and
monoterpenes (13 compounds): tricyclene, $\upalpha$-pinene, camphene,
sabinene, $\upbeta$-pinene, $\upbeta$-myrcene, $\upalpha$-phellandrene,
$\upalpha$-terpinene, p-cymene, limonene, $\upbeta$-ocimene,
$\upgamma$-terpinene,  $\upalpha$-terpinolene~\cite{23}. The major
components of essential oil from \textit{C.~xanthorrhiza} are
$\upalpha$-curcumene, $\upbeta$-curcumene, camphor, and 
xanthorrhizol~\cite{23,24}.

A study by Pramono et~al.\ identified the major chemical constituents of
\textit{C.~xanthorrhiza} as xanthorrhizol, $\upalpha$-cedrene,
ar-curcumene, camphor, and  curzerenone~\cite{25}. Among these, the
three most commonly reported compounds are curcumene, camphor, and
xanthorrhizol. This composition differs from the findings of
Akarchariya et~al., who analyzed \textit{C.~xanthorrhiza} originating
from Chiang Mai, Thailand. Their study identified
$\upalpha$-terpinolene, p-cymen-7-ol, p-cymene, and $\upbeta$-pinene as
the main components, with no detection of curcumene or 
\mbox{xanthorrhizol~\cite{26}.}

As previously noted, although \textit{C.~xanthorrhiza} belongs to the
same genus as \textit{C.~longa}, its essential oil composition is
distinct. \textit{C.~xanthorrhiza} is particularly rich in monocyclic
sesquiterpenes, especially curcumene and xanthorrhizol. In contrast to
\textit{C.~longa}, the essential oil of \textit{C.~xanthorrhiza} lacks
$\upalpha$-turmerone and $\upbeta$-turmerone, but contains
xanthorrhizol, which serves as a characteristic marker compound for
\textit{C.~xanthorrhiza}~\cite{27}. However, previous research
conducted by Uehara~\cite{28} reported the presence of nine
sesquiterpenoids, including ar-turmerone, $\upalpha$-turmerone, 
$\upbeta$-turmerone~\cite{28}. 

\subsection{{Curcuminoids} (see  Figure~\myRef{fig3} for chemical
structures)}
Curcuminoids are linear diarylheptanoid compounds comprising curcumin
and its structural analogs. The primary curcuminoids include curcumin,
monodemethoxycurcumin, bisdemethoxycurcumin,~1-(4
hydroxy-3,5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-(1E,6E)-1,6-heptadiene-\unskip\break3,4-dione,
dihydrocurcumin, and {hexahydrocurcumin} \cite{11,29,30}.
Erpina~\cite{31}
identified~demethoxycurcumin~and~bisdemethoxycurcumin~in 
\textit{C.~xanthorrhiza}, noting that the concentration of
demethoxycurcumin exceeded that of  bisdemethoxycurcumin~\cite{31}.

\begin{figure*}
\vspace*{-1pt}
\includegraphics{fig03}
\vspace*{-1pt}
\caption{\label{fig3}Chemical structure of curcuminoids present in
\textit{C.~xanthorrhiza}.}
\vspace*{-1pt}
\end{figure*}

\section{Hepatoprotective activity}\label{sec5}  
Hepatoprotection refers to the protection of the liver's vital
functions---a critical organ central to most physiological
processes---through pharmacological or other interventions~\cite{32}.
It involves the use of chemical agents to restore normal levels of
catalase, glutathione peroxidase, and superoxide dismutase activity,
thereby safeguarding liver integrity~\cite{33}. This hepatoprotective
effect is attributed to the presence of antioxidant compounds and their
capacity to suppress proinflammatory cytokine activation. Liver injury
often arises from dysfunction of essential cellular organelles,
triggering excessive reactive oxygen species (ROS) production and
subsequent intracellular oxidative stress. ROS-derived free radicals
and lipid peroxidation products are key contributors to the
pathogenesis of liver fibrosis, hepatocyte necrosis, and hepatic
damage~\cite{34,35}.

Pretreatment with \textit{C.~xanthorrhiza} prior to liver injury
demonstrated significant improvement in hepatic biochemical parameters.
This was evidenced by reduced serum levels of liver enzymes, including
alanine transaminase (ALT), aspartate transaminase (AST), alkaline
phosphatase (ALP), serum glutamic-oxaloacetic transaminase (SGOT), and
serum glutamic-pyruvic transaminase (SGPT), collectively contributing
to its hepatoprotective  activity~\cite{36}. Furthermore, 
\textit{C.~xanthorrhiza} administration enhanced hepatic antioxidant defenses
through elevated activity of superoxide dismutase (SOD), catalase
(CAT), and glutathione peroxidase (GPx). This was accompanied by a
reduction in lipid peroxidation, as indicated by decreased
malondialdehyde (MDA) levels, and promoted histological recovery of
liver tissue.

Li  et~al.~\cite{37} examined the dose-dependent hepatoprotective
effects of \mbox{\textit{Curcuma xanthorrhiza}}
against acute hepatotoxicity
induced by D-galactosamine (288~mg/kg, intraperitoneal [i.p.]) in rats,
along with its underlying mechanism of action. Following experimental
protocols, \textit{C.~xanthorrhiza}~extract (100~mg/kg) was
administered orally (p.o.) prior to a single i.p.\ dose of hepatotoxin.
The results demonstrated that~\textit{C.~xanthorrhiza}~treatment
significantly attenuated the acute elevation of serum transaminases
induced by hepatotoxin exposure and markedly reduced the severity of
hepatic damage observed 24~h post-hepatotoxin administration. 

Devaraj  et~al.~\cite{38} conducted a hepatoprotective study on carbon
tetrachloride (CCl$_{4}$)-induced liver damage in rats using hexane
fractions at doses of 125, 250, and 500~mg/kg. The hexane fraction of
\textit{C.~xanthorrhiza} exhibited the highest antioxidant activity.
Regarding hepatoprotective effects, the hexane fraction of 
\textit{C.~xanthorrhiza} demonstrated significant improvements in
biochemical liver function markers, antioxidant enzyme levels, and
lipid peroxidation activity. Histological analysis also revealed
notable recovery in the liver tissues of treated animals. 

\subsection{{Xanthorrhizol}}
Xanthorrhizol is a bisabolane-type sesquiterpenoid compound 
(Figure~\ref{fig4}) extracted from~\textit{Curcuma xanthorrhiza}~Roxb.
This compound has been shown to \mbox{exhibit} various biological activities,
such as anticancer, antimicrobial, anti-inflammatory, antioxidant,
antihyperglycemic, antihypertensive, antiplatelet, nephroprotective,
hepatoprotective, \mbox{estrogenic,} and antiestrogenic effects. These
activities may be attributed to its antioxidant properties and its
ability to modulate the expression and activity of key inflammatory
mediators, including pro-inflammatory cytokines [interleukin
(IL)-1$\upbeta$, IL-6, tumor necrosis factor-$\upalpha$, matrix
metalloproteinases], mediators (cyclooxygenase-2 and inducible nitric
oxide synthase), transcription factors (nuclear factor-kappa B
[NF-$\upkappa$B] and nuclear factor of activated T cells c1), as well
as to regulate diverse signaling pathways involved in 
inflammation~\cite{36,39}.

\begin{figure}
\includegraphics{fig04}
\caption{\label{fig4}Chemical structure of xanthorrhizol.}
\end{figure}

The hepatoprotective effect of xanthorrhizol was evaluated in male ICR
(CD-1) mice treated with cisplatin. Cisplatin is a widely used
anticancer drug; however, at high doses, it can cause undesirable side
effects such as hepatotoxicity. 

The mechanism of protection by xanthorrhizol against cisplatin-induced
hepatotoxicity was reported by Hong  et~al.~\cite{40} Pretreatment with
xanthorrhizol in the liver was associated with the regulation of c-Jun
N-terminal kinase (JNK) phosphorylation. Cisplatin-induced JNK
phosphorylation, particularly JNK1, was significantly attenuated by
xanthorrhizol pretreatment. This finding suggests that JNK
phosphorylation may be involved in the protective effect of
xanthorrhizol against cisplatin-induced hepatotoxicity and may also
influence gene transcription by partially modulating the expression of
transcription factor subunits such as c-Fos and p50.

Although studies on the hepatoprotective activity of xanthorrhizol are
far more limited compared to curcumin, existing evidence suggests that
xanthorrhizol exerts superior suppressive effects against
cisplatin-induced nephrotoxicity and hepatotoxicity. At equivalent
doses, curcumin demonstrates reduced efficacy in attenuating the
elevation of blood urea nitrogen and serum creatinine 
levels~\cite{39}. Molecular pathways in inflammation modulated by
\mbox{xanthorrizol} are shown in  Figure~\ref{fig5}. 

\begin{figure*}
\includegraphics{fig05}
\caption{\label{fig5}Molecular pathways in inflammation modulated by
xanthorrizol and curcumin.}
\end{figure*}

\subsection{{Curcumin derivatives (curcuminoids)}}
The primary curcuminoids that have biological activities
include~curcumin, demethoxycurcumin, bisdemethoxycurcumin (chemical
structures in  
\mbox{Figure~\ref{fig6}}). Curcumin is a hydrophobic polyphenol
derived from the rhizome of~\textit{Curcuma}~species. This compound
exhibits diverse pharmacological properties, including
anti-inflammatory, antioxidative, antinociceptive, antiparasitic, and
antimalarial effects, as well as wound-healing  activity~\cite{41}.
Current research extensively discusses its health benefits,
particularly its protective and preventive effects against cancers,
diabetes, and various disorders of the liver, nervous system, and
cardiovascular systems, while elucidating potential molecular
mechanisms. The hepatoprotective effects of curcumin are mediated
through multiple pharmacological actions, most notably its potent
antioxidant, anti-inflammatory, antifibrotic, and hypolipidemic 
activities~\cite{42,43}.

\begin{figure*}
\includegraphics{fig06}
\caption{\label{fig6}Chemical structure of curcumin derivatives.}
\end{figure*}

The molecular mechanism of curcumin's hepatoprotective action is
mediated through its antioxidant properties and inhibitory activity
against nuclear factor (NF)-$\upkappa$B, which regulates various
proinflammatory and profibrotic  cytokines~\cite{44}. Collectively,
scientific evidence demonstrates that curcumin possesses significant
therapeutic potential for treating liver  disorders~\cite{45}. Curcumin
was identified as a potent inhibitor of rat liver P450 1A1/1A2,
measured as ethoxyresorufin-O-deethylase (EROD) activity in
$\upbeta$-naphthoflavone ($\upbeta$-NF)-induced microsomes. Curcumin
strongly inhibited glutathione S-transferase (GST) activity in the
cytosol of rat liver treated with phenobarbital (PB),
$\upbeta$-naphthoflavone ($\upbeta$-NF), and pyrazole (Pyr), using
1-chloro-2,4-dinitrobenzene (CDNB) as the  substrate~\cite{46}.

Curcumin demonstrates inhibitory effects on hepatic lipid accumulation.
Male ICR (CD-1) mice were fed a bisphenol A (BPA)-contaminated diet
supplemented with or without curcumin for 24 weeks. Curcumin
supplementation significantly ameliorated BPA-induced hepatic fat
accumulation and liver  steatosis~\cite{47}. Curcumin inhibits
platinum-induced hepatic stellate cell activation by downregulating
transforming growth factor-beta (TGF-$\upbeta$) signaling and
suppressing collagen synthesis, thereby preventing liver fibrosis
progression and preserving hepatic  architecture~\cite{48}. Oral
administration of curcumin (300~mg/kg) attenuates liver fibrosis in
BALB/c mice by inhibiting hepatic stellate cell activation and inducing
apoptosis of damaged  hepatocytes~\cite{49}.

Terpene-conjugated curcumin (TCC) was evaluated in an alcoholic liver
disease (ALD) model using 8-week-old male Sprague-Dawley rats. TCC
treatment significantly improved liver function, reduced lipid
accumulation, and alleviated inflammation compared to the model group.
Mechanistically, TCC inhibited the TLR4/MyD88/NF-$\upkappa$B signaling
pathway, decreased endotoxin translocation, enhanced intestinal tight
junction protein expression, and promoted secretory IgA (sIgA) 
production~\cite{50}. Curcumin enhances autophagy (increasing LC3-II
gene expression and decreasing sequestosome 1 (SQSTM1) concentration)
while inhibiting apoptosis (upregulating Bcl-2 gene expression).
High-dose curcumin provides superior protection against liver fibrosis
by significantly reducing ALT, AST, and ALP levels, as well as lipid
peroxidation. Furthermore, curcumin pretreatment increased hepatic heme
oxygenase 1 (HO-1) expression by 2.4-fold while reducing nitric oxide
synthase 2 (NOS-2) expression by  4.1-fold~\cite{51}.

In vitro, 50~$\upmu$M curcumin significantly reduced HepG2 cell
viability and SQSTM1 concentration. These findings suggest that
curcumin and other autophagy activators may be potentially useful for
protection against early-stage hepatocellular carcinoma 
(HCC)~\cite{52}. In another study, curcumin administration prevented
liver damage induced by a cadmium--arsenic mixture. Curcumin treatment
significantly reduced inflammation, oxidative stress, and lipid
peroxidation in mice receiving both cadmium--arsenic and curcumin
compared to those receiving cadmium--arsenic alone. Furthermore,
histological examination of liver tissue revealed that curcumin
treatment resulted in a significant reduction of liver damage observed
in the cadmium--arsenic-exposed  group~\cite{53}. Molecular pathways in
inflammation modulated by curcumin are shown in  Figure~\ref{fig5}.

Demethoxycurcumin~and~bisdemethoxycurcumin~are curcuminoid compounds
other than curcumin. These two compounds have been less studied and
reported in the literature regarding their \mbox{bioactivity.}
Demethoxycurcumin and bisdemethoxycurcumin exhibit antioxidant activity
with IC$_{50}$ values of~12.46~and~17.94~$\upmu$g/mL,
respectively. Meanwhile, bisdemethoxycurcumin demonstrates a better
IC50 value than demethoxycurcumin against the~HepG2 cell line 
(64.7~$\upmu$M)~\cite{54}. In other studies,~in vitro models, such as
the~phosphomolybdenum peroxidation~and~linoleic acid methods, were
used. The antioxidant capacity of the extract, expressed as~ascorbic
acid equivalents  ($\upmu$mol/g)~and~butylated hydroxytoluene (BHT),
at~100 ppm, revealed antioxidant activity in the following order (via
linoleic acid peroxidation):~curcumin ${>}$ demethoxycurcumin ${>}$
bisdemethoxycurcumin. The reported results demonstrate the~antioxidant
potential~of each  curcuminoid~\cite{55}.

Lee et~al.~\cite{56}  demonstrated through in vivo studies using
C57BL/6J mouse models that administration of curcumin,
demethoxycurcumin, and bisdemethoxycurcumin significantly reduced
methionine-choline diet-induced lipid accumulation and elevated levels
of triglyceride (TG) and total cholesterol (TC). These three
curcuminoids exhibited hepatoprotective effects in both HepG2 cell
models and methionine-choline diet-induced non-alcoholic fatty liver
disease (NAFLD) models.  Cheon~\cite{57} investigated the protective
activity of~curcumin, demethoxycurcumin, and
bisdemethoxycurcumin~against hepatocyte injury induced by~carbon
tetrachloride (CCl$_{4}$, 10~mM),~tert-butyl hydroperoxide (TBH,
0.5~mM), and~D-galactosamine (GalN,
30~mM).~Curcumin~and~bisdemethoxycurcumin~exhibited strong
hepatoprotective activity. Curcumin inhibited the~CCl$_{4}$-induced
increase in~lactate dehydrogenase (LDH),~alanine aminotransferase
(ALT), and~aspartate aminotransferase (AST)~levels.
In~TBH-induced~injury, curcumin suppressed the elevation
of~ALT~and~AST, while bisdemethoxycurcumin inhibited the increase
in~LDH,~ALT, and~AST~levels. For~GalN-induced~injury, the rise
in~{LDH,~ALT, and~AST}~levels was significantly suppressed
by~bisdemethoxycurcumin. 

\section{Conclusion}\label{sec6} 

\textit{C.~xanthorrhiza}~has been traditionally used for generations.
Both traditional medicinal practices and scientific studies indicate
its hepatoprotective properties against liver damage. Active compounds
such as xanthorrhizol and curcuminoids (including curcumin and
bisdemethoxycurcumin) are strongly suggested to mediate these
protective effects. However, despite its widespread use, further
research is still required to fully understand the potential side
effects associated with~\textit{C.~xanthorrhiza}~consumption.

\section*{Declaration of interests}
The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

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