This article is mentioned in:

Introduction

Liver cancer is a malignant tumor that poses a serious threat to human health. According to statistics, there are ~700,000 new cases of liver cancer worldwide every year. Data released by the International Agency for Research on Cancer of the World Health Organization show that in 2022, there were an estimated 900,000 new cases of liver cancer worldwide. The incidence rate of liver cancer ranks sixth among malignant tumors and has become the third leading cause of death in the world, with 830,000 deaths per year (1). Among them, the number of new cases and deaths of liver cancer in China is close to half of the total. Hepatocellular carcinoma (HCC) is the fourth most common malignant tumor and the second leading cause of cancer death in China. In 2022, there were 316,500 deaths due to primary liver cancer, ranking second in both the number of deaths and mortality rate. The etiology of liver cancer is diverse and complex and it is currently thought to be related to hepatitis virus infection, alcohol, nitrosamine substances, aflatoxin and certain chemical carcinogens (2). In addition to traditional liver tumor resection, further treatment methods for liver cancer, including interventional therapy, radiofrequency ablation, immunotherapy, targeted therapy, hyperthermic perfusion therapy and liver transplantation, have developed rapidly in recent years (3). Due to its difficult initial diagnosis, rapid progress, significant risk factors after surgery and poor prognosis (4), most patients with liver cancer have missed the opportunity for radical surgery at the time of clinical diagnosis and liver cancer still has the possibility of further development, recurrence and metastasis after palliative surgery. Immunotherapy and targeted therapy are expensive and have not been popularized to date.

Primary prevention of liver cancer and the search for new therapeutic drugs are the current research hotspots. Although aspirin, sorafenib, regorafenib, lenvatinib and other anti-liver cancer drugs are effective therapeutic drugs in clinical practice, they still have shortcomings such as low efficacy, serious side effects and drug resistance (5-7). Although chemotherapy and immunotherapy are conventional options for treatment, they have large toxic and side effects, while natural products have lower systemic toxicity and fewer side effects, which can provide better treatment options for patients (8,9) and have unique advantages in the treatment of liver cancer.

Natural products have played an important role in medicine, particularly in the treatment of chronic and metabolic diseases, and are the basis of most early drugs (10). Some of the world's best-known drugs, including artemisinin, berberine, paclitaxel and elemene, are compounds of natural origin (11). With the development of natural medicinal chemistry technology, the determination of phytochemical compositions and its application in drug development have become possible. In the nearly 20 years, natural products still exist as sources of new drugs and have a large share in new drug discovery (12). Terpenoids are a class of active natural products with a wide range of pharmacological effects and represent a rich library of candidate compounds for drug discovery (13). Terpenoids can be divided into several subclasses according to their chemical structures, including semi-terpenoids, monoterpenoids, sesquiterpenoids, diterpenoids, ester terpenoids and triterpenoids. Among them, the most distributed class of sesquiterpenoids is mainly divided into acyclic, monocyclic, bicyclic, tricyclic and tetracyclic sesquiterpenoids. They can also be divided into five-membered ring, six-membered ring and seven-membered ring sesquiterpenoids by the number of carbon atoms. Furthermore, it can be divided into sesquiterpene alcohols, sesquiterpene ketones and sesquiterpene lactones according to different oxygen-containing groups (14). Various studies have shown that sesquiterpenoid exhibits potential therapeutic effects in anti-tumor, anti-inflammatory, antibacterial and anti-cardiovascular diseases (15-22), and there are more new components and physiological activities to be explored. There have been numerous studies on the application of sesquiterpenoids in HCC, but there is still a lack of systematic analysis of their therapeutic applications. In the present review, the research progress of natural products in the treatment of liver cancer in the past two decades was summarized.

Methods

Prior to 2003, due to technical limitations, the literature records were incomplete or difficult to obtain. A 20-year span is sufficient to present the development process of this field from initial exploration to in-depth research, facilitating the sorting of trends and key nodes; balancing research resources and energy constraints, with a moderate duration for detailed analysis of literature, to avoid an overly broad or narrow scope. Adapting to the changes in liver cancer treatment concepts, technologies and drugs, it is conducive to study the effects of sesquiterpenes in combination with disease characteristics. At the same time, it complies with the standards and regulations of the medical research industry, making it easy to compare and communicate with similar studies. Due to the above reasons, the PubMed (https://pubmed.ncbi.nlm.nih.gov/), Web of Science (https://www.webofscience.com/), Science Direct (https://www.sciencedirect.com) and Springer databases (https://link.springer.com/) were searched for information on sesquiterpenes for the treatment of HCC from 2003 to 2024. The search terms were 'sesquiterpenoid compound', 'sesquiterpene lactone', 'sesquiterpene', 'turmeric', 'curcuma zedoary', 'Artemisia', 'atractylodes rhizome' and 'liver cancer', 'hepatocellular carcinoma' and 'HCC'. The keyword combinations 'liver cancer AND natural sesquiterpenes' and 'hepatocellular carcinoma and natural sesquiterpenes' were used to find relevant articles. The inclusion criteria were as follows: i) Studies with in vivo animal experiments showing the anticancer efficacy of natural sesquiterpenes against HCC; ii) clinical trials concerning the therapeutic benefit of HCC; and iii) original research papers written in English. Review articles, meta-analyses, cross-sectional studies, descriptive studies, studies that did not provide sample data of cancer patients and projects that used secondary data were excluded from this review.

Previous studies were excluded from the review if they were found to have major methodologic errors or lack scientific merit. To aid in classification efforts, studies on mixtures of different compounds or crude extracts were excluded from this study, except for chemically ambiguous sesquiterpenoids. Not all pharmacological effects of sesquiterpenoids have been described in detail in the literature. For instance, the mechanism by which artemisinin exerts its specific anti-HCC activity is still elusive, which may limit its further development in the clinic. Therefore, based on the results of the literature search, a secondary literature search was performed for certain specific medicinal plants obtained, and the search terms were the names of representative compounds, including 'artemisinin', 'elemene' and 'parthenolide'. The gaps of the first search were supplemented and the research system was markedly enriched. Those reviews also includes compounds with undescribed mechanisms that nevertheless have inhibitory effects on HCC cells, providing a more comprehensive anti-liver cancer research direction for the future. Finally, 46 sesquiterpenoids were obtained.

Results

Increasing evidence has shown that sesquiterpenoids can effectively inhibit the progression of HCC and play a therapeutic role in different stages of the disease. It can effectively treat HCC by improving antioxidant capacity, enhancing specific and non-specific immune function, inhibiting cell proliferation and promoting cell apoptosis. The molecular structure of sesquiterpenoids is presented in Fig. 1. Schematics illustrating pathways included in the mechanisms of action of various sesquiterpenoids in HCC are provided in Figs. 2 and 3. The basic information of various natural sesquiterpenoids, including their source, molecular formula and molecular mass, was presented in Table I. It summarizes the activity features of the sesquiterpenoids, including IC50 and dosage, mechanism of action and effects (Table II).

Figure 1 Chemical structures of sesquiterpenoids.

Figure 2 Mechanistic pathways of sesquiterpenoids in hepatocellular carcinoma. (A) Gingerone, (B) Santamarine, (C) Germacenone and (D) Linalool (figure was drawn with Figdraw). PDK1, protein kinase domain containing 1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol(4,5)bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; mTORC2, mammalian target of rapamycin complex 2; AKT(PKB), protein kinase B; MDM2, mdm2 proto-oncogene. TNF-α, tumor necrosis factor-α. TRADD, tumor necrosis factor receptor 1-associated death domain protein; TRAF2/5, tumor necrosis factor receptor-associated factor 2/5; RIP1, receptor interacting serine/threonine-protein kinase 1; TAK1, thymidine kinase 1; IKKβ, inhibitor of κB kinase β; IκB-α, inhibitor of nuclear factor κB α; IL-1β, interleukin-1β; NF-κB, nuclear factor-κB; Bcl-2, B-cell lymphoma-2; ROS, reactive oxygen species; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; AMPK, adenosinemonophosphate-activated protein kinase; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase kinase; GSH, glutathione; NADH, nicotinamide adenine dinucleotide; ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD+, nicotinamide adenine dinucleotide; RTS, radiation therapy simulation.

Figure 3 Mechanistic pathways of sesquiterpenoids in hepatocellular carcinoma. (A) Hinesol, (B) Ar-turmerone, (C) Xanthatin and (D) α-bisabolol (figure was drawn with Figdraw). GRB2, growth factor receptor-bound protein 2; SOS, suppressor of tumorigenicity 1; RAS, rat sarcoma; GTR, G-protein coupled receptors; GDP, GDP-D-mannose pyrophosphorylase; RAF, rapidly accelerated fibrosarcoma; MEK/MAPKK, MAPK kinase; ERK, extracellular signal-regulated kinase; MAPKKK, MAPK kinase kinase; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; MSK1/2, mitogen- and stress-activated protein kinases; Erk1/2, extracellular signal-regulated kinase; ASK1, apoptosis signal-regulating kinase 1; MT, metallothionein; MKK4/7, MAPK kinase 4/7; JNK, c-Jun N-terminal kinase; ER, endoplasmic reticulum; BIP, binding immunoglobulin protein; CHOP, C/EBP homologous protein; ATF4, activating transcription factor 4; PERK, protein kinase R-like endoplasmic reticulum kinase; eIF2α, eukaryotic translation initiation factor 2α; FADD, fas-associating protein with a novel death domain; Bid, BH3-interacting domain death agonist; Bax, BCL2-associated X; Bcl-2, B-cell lymphoma-2; Cyt c, cytochrome C; Caspase-3, cysteinyl aspartate-specific proteinase-3.

Table I Basic information on various natural sesquiterpenoids.

Table I

Basic information on various natural sesquiterpenoids.

Name of compound	Molecular formula	Relative molecular mass	Source	(Refs.)
Acorusin E	C15H22O5	282	Acori tatarinowii rhizoma	(150)
Ar-turmerone	C15H20O	236	Turmeric	(104)
Artemeriopodin G7	C29H36O6	516	Artemisia australis	(135)
Artemiprincepsolides A	C30H38O6	539	Artemisia princeps	(78)
Artemongolins E	C31H39O8	539	Artemisia mongolica	(155)
Artemisacrolide B	C19H24O5	377	Artemisia sacrorum	(157)
Artemisinin	C15H22O5	284	Artemisia apiacea	(27)
Artemyriantholide E	C30H33O6Cl	523	Artemisia lactiflora	(156)
Artesunate	C19H28O8	380	Artemisia apiacea	(30)
Atractylon	C15H20O	236	Rhizoma atractylodis	(99)
Bigelovin	C17H20O5	324	Inula flower	(43)
Britanin	C19H26O7	366	Inula flower	(42)
Carpespene A	C15H18O3	264	Carpesium faberi, Guizhou	(79)
Cis-Nerolidol	C15H26O	222	Natural products found in essential oils such as bitter neroli oil and Peruvian balm oil	(90)
Costunolide	C12H20O2	216	Costustoot	(40)
Cryptomeridiol	C15H28O2	260	Mangnolia officinalis	(142)
Curcumenol	C15H24O2	260	Curcuma zedoary	(119)
Dehydrocostus lactone	C15H18O2	248	Inula racemosa	(39)
Deoxyelephantopin	C19H20O6	364	Elephantopus scaber	(59)
Dihydroartemisinin	C15H24O5	288	Artemisia apiacea	(28)
Dimethylaminomicheliolide	C17H28ClNO3	339	Michelia L.	(50)
Elemene	C15H24	228	Curcuma zedoary	(146)
Furanodiene	C15H20O	232	Curcuma zedoary	(143)
Germacrone	C15H22O	236	Curcuma zedoary	(97)
Hemistepsin A	C18H20O6	352	Hemistepta lyrata	(66)
Hinesol	C15H26O	244	Rhizoma atractylodis	(115)
Hirsutanol A	C14H18O3	252	Endophytic bacteria of soft corals	(144)
Isoalantolactone	C15H20O2	252	Elecampane	(37)
Lavandiolide H	C30H38O6	494	Artemisia atrovirens	(33)
Lavandiolide I	C30H36O6	492	Artemisia	(158)
Linalool	C10H18O	172	Coriandrum sativum L.	(84)
Micheliolide	C15H20O3	268	Michelia L.	(47)
Narjatamolide	C19H24O4	316	Rhizome of Pinus officinalis	(44)
Parthenolide	C15H20O3	268	White daisy	(45)
Santamarine	C15H20O3	268	Aplotaxis auriculata	(65)
Scabertopinolide G	C20H22O7	397	Elephantopus scaber	(63)
Senedensiscin G	C28H46O10	542	Senedensiscin	(152)
Sulfoscorzonin E	C19H27O6NS	397	Scorzonera divaricata	(153)
Thapsigargin	C34H50O12	652	Thapsia garganica	(105)
Telekin	C15H20O3	268	Carpesium divaricatum	(77)
Xanthatin	C15H18O3	264	Xanthium	(72)
Xanthorrhizol	C15H22O	236	Turmeric	(88)
Zerumbone	C15H22O	236	Zingiber zerumbet	(129)
(2S,7R,10S)-3-hydroxypseudotigerone 11-O-β-D-glucopyranoside	C21H34O8	416	Atractylis lancea rhizome	(111)
β-elemene	C15H24	228	Curcuma zedoary	(149)
α-bisabolol	C15H26O	222	Chamomile	(94)

Table II Mechanisms of action of sesquiterpenoids against hepatocellular carcinoma.

Table II

Mechanisms of action of sesquiterpenoids against hepatocellular carcinoma.

Sesquiterpene compound	IC50	Effective dose	Pathways	Observed effects	(Refs.)
Artemisinin	250 μM (HepG2), 290 μM (SMMC-7721)	-	via TIMP2 protein↑ and matrix metalloproteinase 2 protein↓	Inhibited the migration and invasion of HepG2 and SMMC-7721 cells	(35)
Dihydroartemisinin	-	20 and 40 μM	via inhibition of cyclin B and cdc25c, G2/M phase arrest	Apoptosis of HepG2 and Hep3B cells was induced	(36)
Artesunate	20 μM	-	via STAT3, PI3K/AKT/mTOR pathway	The activity of HepG2 cells was inhibited	(39)
Lavandiolide H	3.8 μM (HepG2), 4.6 μM (SMMC-7721), 4.5 μM (Huh7)	-	Bcl-2 protein↓ and PARP-1↑	Inhibited the proliferation of HepG2, SMMC-7721 and Huh7 cells	(43)
Isoalantolactone	71.2 μM (12 h), 53.4 μM (24 h)	-	via Ras/Raf/MEK	Inhibition of HepG2 cell proliferation	(45)
Dehydrocostus lactone	20.33 μM	-	via PI3K/AKT	Inhibition of HepG2 cell proliferation	(46)
Costunolide	18.09±1.74 μM	-	Bax protein↑, caspase-3↑, caspase-8↑, caspase-9↑ and Bcl-2 protein↓	Promoted HepG2 cell apoptosis	(48)
Britanin	27.86±1.35 μM (HepG2), 28.92±1.09 μM (SMMC-7721), 15.69±1.58 μM (Huh7)	-	via AMPK was regulated by activation of ROS	Induced apoptosis and autophagy in HepG2, SMMC-7721 and Huh7 cells	(49)
Bigelovin	-	5 and 10 μM	Caspase-3↑ and PARP-1↑	Induced apoptosis of HepG2 and SMMC-7721 cells	(50)
Narjatamolide	5.67±1.43 μM	-	via induced cell cycle arrest at G2/M phase	Inhibition of BEL-7402 cell proliferation	(51)
Parthenolide	-	-	ROS is generated, resulting in blocking of the cell cycle	Apoptosis and autophagy in HepG2 cells	(53)
Micheliolide	31.46±5.33 μM (24 h), 13.4±1.39 μM (48 h), 8.13±1.29 μM (72 h)	-	ROS inhibition normalized MCL-induced ERS	inhibited the development of hepatoma organoids	(56)
DMAMCL	12.74±0.72 μM (HepG2), 13.82±0.54 μM (Hep3B), 12.91±0.83 μM (Huh7), 17.21±0.68 μM (SMMC-7221)	-	via PI3K/AKT	Apoptosis of HepG2, SMMC-7721, Hep3B and Huh7 cell lines	(62)
Deoxyelephantopin	40 μM	-	via NF-κB	Inhibition of HepG2 cell proliferation and induction of apoptosis	(69)
Scabertopinolide G	7.0-10.3 μM	-	via increased ROS production and decreased MMP	Autophagy was induced in Hep3B and HepG2 cells	(70)
Santamarine	70 μM	-	via NF-κB	Inhibition of HepG2 cell proliferation and induction of apoptosis	(72)
Hemistepsin A	15.27±1.84 μM (Huh7), 26.5±6.07 μM (HepG2)	-	via AMP/AMPK, STAT3	Slowed down the cell cycle progression of Huh7 and HepG2 cells and induced apoptosis	(77)
Xanthatin	-	20 and 40 μM	via PERK-eIF2α-ATF4 signaling pathway and target CHOP	Apoptosis of HepG2, Bel-7402 and SMMC-7721 hepatoma cells	(82)
Telekin	3.75-30 μM	-	via activation of p38 and MAPKAPK-2 pathways	Inhibition of HepG2 cell viability and induction of apoptosis	(84)
Artemiprincepsolides A	9.9 μM	-	Bc1-2 protein↓ and Bax protein↑	Induced apoptosis of HepG2 cells	(85)
Carpespene A	5.17 μM	-	via triggering excess ROS	Apoptosis of HepG2 cells	(90)
Linalool	-	2 μM	via inhibition of mitochondrial complex I and II activity	The viability of HepG2 cells was reduced	(94)
Xanthorrhizol	4.17 μg/ml	-	Promoted the proteolytic cleavage of PARP and ICAD, Bcl-2 and Bcl-xl protein↓	Induced apoptosis of HepG2 cells	(96)
Cis-Nerolidol	-	150 μM	via mitochondrial membrane potential by arresting the cell cycle in G1 phase	Cell death was induced in HepG2/C3A cells	(100)
α-bisabolol	-	-	via NF-κB	Apoptosis of HepG2 cancer cells	(102)
Germacrone	-	240 μM	via STAT3 and JAK2	Induced apoptosis of HepG2 cells	(105)
Atractylon	26.19 μM (HepG2), 22.32 μM (SMCC7721), 34.14 μM (MHCC97H)	-	via mitochondrial apoptosis pathway	Induced apoptosis of HepG2, SMCC7721 and MHCC9H cells	(109)
Ar-turmerone	64.8±7.1 μg/ml (HepG2), 102.5±11.5 μg/ml (Huh-7), 122.2±7.6 μg/ml (Hep3B)	-	via ERK/JNK	Apoptosis of HepG2, Huh-7 and Hep3B cells	(111)
Thapsigargin	-	1, 2, 4, 8 μM	via inhibition of SERCA-ATPase in hepatoma cells and depletion of intracellular Ca2+ pool	Apoptosis of hepatoma cells	(115)
(2S,7R,10S)-3-hydroxypseudotigerone-11-O-β-D-glucopyranoside	-	10 μmol/l	-	Significant protective effect on HepG2 cell injury induced by N-acetyl-p-aminophenol	(121)
Hinesol	-	-	via MAPK and ERK; NF-κB	Inhibition of proliferation and induction of apoptosis in SMMC-7721 and LM3 cells	(124)
Curcumenol	-	-	via DJ-1, PTEN, PI3K/AKT signal transduction pathway	Inhibition of the proliferation of HepG2 hepatoma cells	(137)
Zerumbone	6.20±0.7 μg/ml	12.5 μg/ml	MMP-9, VEGF and VEGF receptor proteins↓	Induced apoptosis of HepG2 cells	(138)
Artemeriopodin G7	16.0 μM	-	CDC2 and p-CDC2 protein expression↓, it targets PDGFRA, affects AKT/STAT signaling and induces G2/M cell cycle arrest	Inhibition of HepG2 cell migration and invasion, and induction of apoptosis	(147)
Cryptomeridiol	>50 μM	-	via IRE1α-ASK1-JNK, resulting in loss of MMP	The viability of HepG2, Hep3B and Huh-7 cells was reduced	(148)
Furanodiene	70 μg/ml	300 μM	via mitochondrial caspase apoptosis and ERK/MAPK signals	Inhibition of HepG2 cell growth and induction apoptosis	(149)
Hirsutanol A	14.54 (24 h), 6.71 (48 h), 3.59 (72 h) μmol/l	-	via activated ROS	Autophagic cell death was induced in Hep3B hepatoma cells	(150, 151)
Elemene	63±2.1 μg/ml	-	GSTP1 gene methylation was reversed and cell cycle was inhibited	Induced apoptosis of QGY7703 cells	(155)
β-elemene	-	100 μg/ml	Downregulation of c-Met expression	Inhibited the growth of H22 hepatoma cells	(156)
Acorusin E	2.11-7.99 μM	-	-	Apoptosis of SMMC-7721 cells	(157)
Senedensiscin G	9.5-11.5 μM	-	-	Showed inhibitory activity on SMMC-7721 cells	(159)
Sulfoscorzonin E	4.21±0.56 μg/ml	-	-	Moderate cytotoxic activity on HepG2 cells	(161)
Artemongolins E	88.6 μM (HepG2), 59.1 μM (Huh7), 67.5 μM (SK-Hep-1)	-	-	The inhibitory effect on HepG2, Huh7 and SK-Hep-1 cells was significant	(162)
Artemyriantholide E	14.2 μM (HepG2), 9.0 μM (Huh7), 8.8 μM (SK-Hep-1)	-	MAP2K2 may be a core gene	Good inhibitory activity against HepG2, Huh7 and SK-Hep-1 cells	(163)
Artemisacrolide B	21.9 μM (HepG2), 8.2 μM (Huh7), 16.9 μM (SK-Hep-1)	200 μg/ml	-	Marked anti-liver cancer activity against HepG2, Huh7 and SK-Hep-1 cells	(164)
Lavandiolide I	12.1 μM (HepG2) 18.4 μM (Huh7), 17.6 μM (SK-Hep-1)	-	-	Marked anti-liver cancer activity against HepG2, Huh7 and SK-Hep-1 cells	(165)

[i] ↑, upregulation; ↓, downregulation; ROS, reactive oxygen species; TIMP2, tissue inhibitors of metalloproteinase 2; STAT3, signal transducers and activators of transcription; PI3K, phosphatidylinositol-3-hydroxykinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; Bcl-2, B-cell lymphoma/leukemia-2; PARP-1, polymerase 1; Ras, rat sarcoma; Raf, rapidly accelerated fibrosarcoma; MEK, MAPK kinase; Bax, Bcl-2-associated X-protein; caspase-3, procysteinyl aspartate-specific proteinase-3; AMPK, adenosine monophosphate-activated protein kinase; ERS, endoplasmic reticulum stress; NF-κB, nuclear factor-κB; MMP, mitochondrial membrane potential; AMP, adenosine monophosphate; PERK, protein kinase r-like endoplasmic reticulum kinase; eIF2α, eukaryotic translation initiation factor 2α; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; MAPKAPK-2, MAPK activated protein kinase 2; PARP, poly(adenosine diphosphate-ribose) polymerase; ICAD, inhibitor of caspase-activated deoxyribonuclease; JAK2, Janus kinase 2; SERCA-ATPase, sarcoplasmic reticulum calcium pumps; MAPK, mitogen-activated protein kinases; ERK, extracellular signal-regulated kinase; PTEN, phosphatase and tensin homolog; DJ-1, Parkinson disease protein DJ-1; VEGF, vascular endothelial growth factor; PDGFRA, platelet-derived growth factor receptor A; IRE1α, inositol-requiring enzyme 1α; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; GSTP1, glutathione S-transferase Pi 1; MAP2K2, MAPK kinase 2.

Sesquiterpene lactones

Sesquiterpene lactones are the most studied sesquiterpene compounds at present. The chemical structure of sesquiterpene lactones is based on a skeleton of 15 carbon atoms and consists of three cyclic isoprene structures, one of which is a five-membered (γ-) lactone group (cycloester) (23). This unique structure makes sesquiterpene lactones have a variety of biological activities. Previous studies have shown that α-methylene-lactones of this kind of compounds have anti-tumor activity, while α- and β-unsaturated lactones have strong anti-inflammatory activity (24-26). Depending on the carboxy skeleton and the type and position of the substituent, sesquiterpene lactones can be divided into different subgroups, including the germacranolides, guaianolides, pseudoguaianolides, eudesmanolides and elemanolides. In recent years, it has been found that sesquiterpene lactones with anti-tumor activity are mainly derived from artemisinins, alantolides, descholinolides and parthenolides.

Artemisinin and its derivatives

Sesquiterpenoids, particularly guaiacolactone, artemisia, absinthium, sterolactone and barley fructosterol lactone, are the main chemical components of Artemisia, and some of them have shown a variety of significant biological activities, including anti-tumor, anti-malaria, anti-inflammatory, immunomodulatory, anti-ulcer, anti-parasite and anti-bacterial (27).

The main component of the Artemisia and its derivatives is artemisinin, dihydroartemisinin and artesunate are derivatives of artemisinin, have strong anti-tumor activity. The anticancer properties of artemisinin result from its unique chemical structure, particularly its internal peroxide bridge structure, which is critical for its biological activity. Its mechanism of action mainly involves the generation of reactive oxygen species (ROS) after interaction with intracellular iron (28). Cancer cells, including HCC, exhibit an abnormal iron metabolism, as indicated by elevated transferrin receptor expression and iron accumulation. This dependence makes them more vulnerable to oxidative damage caused by ROS (29). Upon iron activation, artemisinin produces cytotoxic free radicals that target cellular macromolecules, leading to apoptosis and ferroptosis (30). Artemisinin has been shown in studies of HCC to induce mitochondrial dysfunction, disrupting cellular respiration and energy production. In addition, it can regulate key signaling pathways, including the phosphatidylinositol-3-hydroxykinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis, thereby inhibiting cell proliferation and enhancing apoptosis (31). Another key mechanism involves the regulation of angiogenesis. Artemisinin has been shown to inhibit vascular endothelial growth factor (VEGF) signaling, which is critical for tumor angiogenesis and metastasis (32). This is particularly important in HCC, which relies heavily on neovascularization for growth and spread. In addition, artemisinin enhances the effects of conventional therapies, potentially reducing drug resistance by making cancer cells more sensitive to chemotherapeutic agents and radiotherapy (33). It is able to reduce the production of inflammatory cytokines and reprogram immune cells, such as the anti-tumor phenotype of macrophages, in a certain direction. These immunomodulatory effects, coupled with its direct cytotoxic effects, enhance its anticancer potential (34). Artemisinin inhibited the migration and invasion of HCC cell lines in a dose- and time-dependent manner. The inhibitory effect of artemisinin on invasion and metastasis of HCC cells is mediated by upregulation of tissue inhibitors of metalloproteinase 2 (TIMP2) and downregulation of matrix metalloproteinase 2 in vitro and in vivo (35).

Dihydroartemisinin significantly inhibited the growth of HCC cells in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis in HCC cell lines. Induction of p21 and inhibition of cyclin B and cell division cycle (CDC)25C contributed to dihydroartemisinin-induced G2/M arrest. Dihydroartemisinin-induced apoptosis was found to be associated with mitochondrial membrane depolarization, cytochrome c release, caspase activation and DNA fragmentation. In addition, dihydroartemisinin was able to inhibit HCC growth in a xenograft mouse model (36).

The mechanisms by which artesunate derivatives inhibit tumor growth are not fully understood, among which the most likely mechanism is that artesunate derivatives exhibit several modes of action against HCC simultaneously in a variety of specific ways. Whether artesunate drugs are used alone or synergistically in combination, the underlying mechanisms are similar and may act in a variety of specific ways, while exhibiting several modes of anti-HCC action. Artesunate is a reduced artemisinin monoester succinate that inhibits the activity of HepG2 and BWTG3 cells in a dose- and time-dependent manner (37). It can induce apoptosis of HCC cells by specifically inhibiting signal transducers and activators of transcription (STAT3) (38). Artesunate interfered with STAT3 dimerization in vitro, inhibited constitutive and I-6-induced STAT3 and then regulated STAT3-dependent procysteinyl aspartate-specific proteinase-3 (caspase-3), B-cell lymphoma/leukemia-2 (Bcl-2)-related X protein (Bcl-xl) and survivin. Another study found that artesunate combined with sorafenib induced apoptosis in HCC cells by inhibiting the PI3K/AKT/mTOR pathway (39).

Lavandiolide H

Guaiacane-type sesquiterpene dimers, which contain a large amount of sesquiterpene lactone, were isolated from Artemisia and acted on three kinds of liver cancer cells (40-42). The results showed that the guaiacolide dimer sesquiterpene Lavandiolide H significantly inhibited the proliferation of three different human hepatoma cell lines. The sesquiterpene also induced G2/M-phase arrest and apoptosis of HepG2 cells and downregulated the expression of the Bcl-2 oncogene and poly(ADP-ribose) polymerase 1 (PARP-1), while upregulating the expression of cleaved PARP-1 (43). The results of this study indicated the potential of guaiactone dimer as a candidate natural small molecule compound for the treatment of HCC.

Isoalantolactone

Isoalantolactone is derived from the dried roots of elecampane, a plant of the genus Inula in Asteraceae, and has wide-ranging therapeutic potential (44). As a promising candidate for cancer research, as well as drug discovery and design, Isoalantolactone exhibits potent anti-proliferative activity against HepG2 cells. By promoting caspase-dependent apoptosis, inducing oxidative stress to inhibit cell migration and cell invasion, and blocking Ras/Raf/MAPK kinase signaling, it induces dose-dependent inhibition of HepG2-cell proliferation (45).

Dehydrocostus lactone

Dehydrocostus lactone is a sesquiterpene lactone with a high content in the essential oil of Inula racemosa and the main bioactive component of Inula racemosa. Dehydrocostus lactone inhibits HepG2 human hepatoblastoma cells by downregulating the PI3K/AKT signaling pathway (46).

Costunolide

Costunolide is one of the main chemical components and quality control components of Costustoot in traditional Chinese medicine. Epidermal growth factor receptor (EGFR) amplification and abnormal activity are closely related to the occurrence and development of a variety of malignant tumors, including liver cancer. Therefore, key molecules in the EGFR signaling pathway are considered important oncogenic factors and key therapeutic targets. Costunolide can increase the ubiquitination of EGFR and reduce the distribution of EGFR recycling to the cell membrane, thereby inhibiting EGF signaling (47). In vitro studies showed that costunolide could inhibit the proliferation and promote apoptosis of HepG2 cells, and cause cell cycle arrest in G2/M phase in a dose-dependent manner, and thus significantly induce apoptosis of HepG2 cells. The mechanism is that costunolide may promote cell apoptosis by upregulating the expression levels of Bcl-2-associated X-protein (Bax), caspase-3, caspase-8 and caspase-9 and downregulating the expression of Bcl-2 protein (48).

Britannin

Phytosterols, flavonoids, sesquiterpene lactones and essential oils are the main chemical constituents of Inula L. Britannin, a compound isolated from Inula L., which can induce apoptosis and autophagy by activating ROS-regulated adenosine monophosphate-activated protein kinase (AMPK) in liver cancer cells. It provides a molecular basis for the development of Britannin as an effective anti-liver cancer drug candidate (49).

Bigelovin

Bigelovin, a sesquiterpene lactone isolated from Inula, has been shown to have apoptosis-inducing, anti-inflammatory and anti-angiogenic activities. Bigelovin was found to have potential antitumor activity against human HCC in vitro and in vivo. Bigelovin inhibited cell proliferation and colony formation. Bigelovin induces apoptosis by promoting the cleavage of caspase-3 and PARP-1. This process is also accompanied by the activation of autophagy, which is manifested as the increase of autophagosomes and the decrease of light chain I protein type 3-II, Beclin-1 and ubiquitin-binding protein p62 (50).

Narjatamolide

Narjatamolide, isolated from rhizoma nardostachyos, exhibits an anti-proliferation effect on BEL-7402 cells in a dose-dependent manner, and the results of cell cycle analysis show that this compound can induce cell cycle arrest in G2/M phase (51).

Parthenolide

Parthenolide is a gemmarane type sesquiterpene lactone natural product extracted from Leucanthemella, which was first isolated from the traditional herbal medicine white daisy in 1965 (52). By inducing the generation of ROS in HepG2 cells, blocking its cell cycle and causing apoptosis and autophagy, it exerts an anti-tumor effect (53).

Micheliolide

Micheliolide is a sesquiterpene lactone natural product isolated from Michelia L. and Michelia x alba (54), which is a guaiacane sesquiterpene in structure. Compared with parthenolide, aconitolide has at least three advantages: High stability, low toxicity and continuous release of active drug (55). Micheliolide as a thioredoxin reductase (TrxR) inhibitor with high potential to induce immunogenic cell death (ICD). The magnitude of ICD-related effects induced by micheliolide exposure in HCC cells was found to depend on the generation of ROS-mediated endoplasmic reticulum (ER) stress (ERS). Furthermore, ROS inhibition normalizes micheliolide-induced ERS, whereas TrxR downregulation acts synergistically with micheliolide-driven ERS, and micheliolide inhibits the development of hepatoma organoids (56).

Dimethylaminomicheliolide

Dimethylaminomicheliolide is a pro-drug of micheliolide, and in normal cells, the former has higher stability, higher activity and lower toxicity than micheliolide. In addition to their anti-tumor effects, micheliolide and dimethylaminomicheliolide also have protective effects against inflammation, hepatic steatosis, diabetic nephropathy and rheumatoid arthritis (57-60). Dimethylaminomicheliolide has minimal side effects in animals and is a safe and promising drug for long-term in vivo treatment (61). Dimethylaminomicheliolide reduced the viability of HCC cells in a dose- and time-dependent manner, and caused cell cycle arrest in G2/M phase and inhibited cell invasion and epithelial-mesenchymal transition (EMT). It also induces cell death through the intrinsic apoptotic pathway of HCC cells, which can be blocked by the caspase inhibitor zVAD-fmk, Bax/Bcl-2 antagonist/killer 1 (Bak) silencing or Bcl-2 overexpression. Dimethylaminomicheliolide inactivates the PI3K/AKT pathway, leading to ROS production, thereby regulating dimethylaminomicheliolide-induced apoptosis (62).

Deoxyelephantopin

Elephantopus scaber's chemical composition is complex and its main components include sesquiterpene lactones, triterpenes, flavonoids, steroids and anthrones. Modern pharmacological studies have shown that it has the effects of liver protection, as well as antibacterial, anti-tumor and anti-inflammatory properties, and may be used in the treatment of diabetes (63-65). Deoxyelephantopin is the main component of Elephantopus scaber (66), which has a variety of biological activities, including antibacterial, anti-diabetic, anti-inflammatory, wound healing, liver protection and anti-cancer activity (67,68). Deoxyelephantopin inhibits the proliferation and induces apoptosis of HepG2 cells in a dose-dependent manner, possibly related to the generation of ROS, glutathione (GSH) depletion and reduced TrxR activity, disrupting the mitochondrial membrane potential (MMP) and enhancing DNA fragmentation. Further studies have shown that deoxyelephantopin can reduce the phosphorylation of inhibitor of nuclear factor κB (NF-κB)α (IκB-α) to inhibit the translocation of constitutive and inducible NF-κB to the nucleus, and exert its anti-cancer effect through oxidative stress. Deoxyelephantopin can be used as a potential drug for effective treatment of liver cancer (69).

Scabertopinolide G

A total of seven new compounds, Scabertopinolide A-G, were isolated from Elephantopus scaber, among which Scabertopinolide G showed the strongest inhibitory effect on the proliferation of three human tumor cell lines, HepG2, Hep3B and MCF-7 (70). Scabertopinolide G induces autophagy in Hep3B and HepG2 cells by increasing ROS production and reducing the MMP. In addition, signaling pathways including MAPK and AKT may play an important role in the induced death of liver cancer cells (71).

Santamarine

Santamarine is one of the effective components of Aplotaxis auriculata. The potential anticancer activity of santamarine was achieved by inhibiting cell proliferation and inducing cell apoptosis. Santamarine inhibited TNF-α-induced translocation of NF-κB to the nucleus by reducing the phosphorylation of IκB-α. In addition, santamarine inhibited STAT3 activation by reducing the phosphorylation of tyrosine 705. Pretreatment with acetylcysteine reversed the effects of santamarine-mediated cell death, NF-κB inhibition and STAT3 activity blockade, suggesting that oxidative stress is involved in santamarine-mediated anticancer activity. The exact molecular mechanism of santamarine-induced apoptosis needs to be further studied to make it a lead drug for the treatment of liver cancer in the future (72).

Hemistepsin A

Hemistepta lyrata is a plant of the Asteraceae family, a wild Korean biennial herb that is traditionally used to treat wounds, fever, bleeding and ulcers. Hemistepsin A, one of the compounds extracted from Hemistepta lyrata, is a potential candidate for the prevention of hepatitis, steatosis and fibrosis (73-76). Hemistepsin A slows down the cell cycle progression of HCC cells and induces cell senescence by activating AMP-activated AMPK (77). Hemistepsin A induces apoptosis of HCC cells by downregulating STAT3 and sensitizing them to conventional chemotherapy drugs (78).

Xanthatin

Xanthatin is a bicyclic sesquiterpene lactone isolated mainly from Xanthium (79). Studies have shown that xanthatin has significant antitumor activity in a variety of cell lines of colon, breast, lung, cervical and skin cancers (80,81). Xanthatin can trigger an ER stress response in HCC cells and the pro-apoptotic effect is related to ER stress. By increasing activating transcription factor 4 (ATF4) in the nucleus, xanthatin promotes the PERK-eIF2α-ATF4 signaling pathway and its downstream target of C/EBP homology protein-mediated ER stress (82,83).

Telekin

Telekin is extracted from the traditional Chinese herb Carpesium divaricatum. It was reported to inhibit HepG2 cell viability and induce apoptosis in a dose-dependent manner. In addition, Telekin treatment induced cell cycle arrest at the G2/M phase, with a significant increase in CDC25A and CDC2 phosphorylation and a decrease in cyclin B1 levels. Telekin induces G2/M phase arrest in hepatoma cells by activating the p38 and mitogen-activated protein kinase activated protein kinase 2 (MAPKAPK2) pathways, and has an inhibitory effect on hepatoma cells (84).

Artemiprincepsolides A

Artemiprincepsolides A-F were isolated from Artemisia princeps, and compounds 1-6 were evaluated for their hepatotoxicity against three hepatoma cell lines. Among them, Artemiprincepsolide A showed significant cytotoxicity against HepG2, Huh7 and SK-Hep-1 cells, which was almost comparable to the positive control sorafenib, inhibited the migration and invasion of HepG2 cells in a dose-dependent manner by downregulating phospho-CDC2 and upregulating cyclin B1 protein levels, and significantly induced G2/M-phase arrest in HepG2 cells. Apoptosis was induced by downregulating the expression of Bc1-2 and upregulating the level of Bax (85).

Carpespene A

The main active components of Carpesium mainly include sesquiterpene lactones and monoterpenoids (86,87), among which sesquiterpene lactones show strong cytotoxic activity (88). Its antitumor activity is reflected in its potent cytotoxic effect on a variety of tumor cell lines and induction of apoptosis in vitro. Among them, the α- and β-unsaturated lactone ring is the key active center (89). A total of 10 previously undescribed sesquiterpenes, carpespenes A-J (nos. 1-10), and eight known compounds (nos. 11-18), were isolated from the whole strain of Carpesium faberi, Guizhou. Carpespene A is an eudesmanolide-type sesquiterpene lactone containing an open five-membered ring of C-2 and C-3. Mechanistically, Carpespene A induced apoptosis in HepG2 cells by triggering excessive ROS accumulation, and ROS-induced cytoprotective autophagy attenuated the cytotoxicity of Carpespene A. Carpespene A also inhibited the anti-phagocytosis and enhanced the cytotoxic effect of ROS on HepG2 cells (90).

Dimethylaminomicheliolide

Dimethylaminomicheliolide is a pro-drug of micheliolide, in normal cells show than micheliolide higher stability.

The active center of sesquiterpene alcohols has a structure of 15 carbon atoms. The six most common sesquiterpene alcohols are farnesol, nerolidol, petrolatol, patchoulic alcohol, santalol and eucalyptol.

Linalool

Coriandrum sativum is used as an appetiser for its flavoured leaves and seeds and is also considered a home remedy in herbal and folk medicine. In addition to its ability to reduce fertility, hyperglycemia, hyperlipidemia and oxidative stress, cilanthus has antibacterial, anxiolytic and sedative effects (91,92). Linalool is the main component of coriandrum sativum and one of the chemicals commonly used in the cosmetics and perfume industries. Safety evaluation studies have shown that linalool is not irritating, phototoxic or allergenic, but has low-grade acute toxicity (93). Linalool reduced HepG2 viability by inhibiting mitochondrial complex I and II activity, increasing ROS and reducing ATP and GSH levels (94).

Xanthorrhizol

Derived from Turmeric, Xanthorrhizol exhibits anti-cancer activity against various types of cancer, liver, lung, breast, cervical and colon cancer, by alleviating angiogenesis and metastasis, activating apoptosis and inducing cell-cycle arrest (95). Xanthorrhizol promoted the proteolytic cleavage of PARP and inhibitor of caspase-activated deoxyribonuclease (ICAD), and concomitantly, the expression of anti-apoptotic Bcl-2 and Bcl-xl was also decreased in HepG2 cells, The above results indicate that xanthorrhizol is an effective anti-liver cancer drug, and its mechanism of action is to induce apoptosis (96).

Cis-Nerolidol

Nerolidol, a compound found in numerous plant species, has received considerable attention in various fields of research due to its anti-inflammatory, anti-leishmaniasis and anti-fungal activities (97,98). Nerolidol is a sesquiterpene and exists in the form of two isomers, cis-nerolidol (C-NER) and trans-nerolidol (99). Only C-NER showed medium cell toxic activity (HepG2/C3A); C-NER did not show genotoxic activity but altered MMP, reduced cell proliferation and induced cell death by arresting the cell cycle at G1 phase (100).

α-Bisabolol

Chamomile is a commonly used medicinal herb in Europe and has historically been used in cosmetics and health foods (101). Its main components are blue balsamol and α-bisabolol. α-Bisabolol is a low-toxicity sesquiterpene that can be used in the pharmaceutical, food and hygiene industries, particularly for topical applications. Using human hepatoma HepG2 cells as a model, higher concentrations of cleaved caspase-3, -8 and -9 were found in α-bisabolol-treated cells compared with untreated cells. In addition, α-bisabolol reduced mitochondrial cytochrome c levels, increased the cytosolic cytochrome c content and upregulated the downregulation of pro-apoptotic proteins Bax and BH3-interacting domain death agonist and the anti-apoptotic Bak and Bcl-2 proteins. After α-bisabolol treatment, the expression of p53, NF-κB and Fas was increased, suggesting that they play a role in mediating α-bisabolol-induced apoptosis in cancer cells (102).

Sesquiterpene ketones

Ketones feature a carbonyl group (C=O) connected to 2 functional groups (R and R'). Sesquiterpene ketones generally contain 15 carbon atoms, and structures with a number between 10 and 15 carbon atoms are also included in this group because of their similar characteristics. Previous studies have shown that sesquiterpenes containing α- and β-unsaturated ketones exhibit significant anti-tumor activities (103).

Germacrones

Germacarones are found in plants from different families, such as Zingeraceae, Geraniaceae and Ericaceae. Currently, germacrone is mainly obtained from Curcuma zedoary, and it can be used as a quality marker component of Curcuma zedoary. Previous studies have shown that germacarone has a significant inhibitory effect on HepG2 and BeL-7402 cells and can induce G2/M-phase arrest of the cell cycle, which is related to the significant reduction of cyclin B1 and cyclin-dependent kinase 1 protein expression and the induction of p21. Dose-related upregulation of Bax and downregulation of Bcl-2/Bcl-xl resulted in an increase in the total number of associated apoptotic cells, as well as upregulation of tumor suppressor gene p53 and increased ROS (104). Germacarone can also reduce the expression of STAT3 and Janus kinase 2 (JAK2), and induce apoptosis of HepG2 cells through the JAK2/STAT3 signaling pathway (105).

Atractylon

Atractylon extracted from Atractylodes Lancea (Thunb.) DC. and Atractylodes macrocephala significantly inhibited proliferation and promoted apoptosis of hepatoblastoma cell lines (106-108). In addition, the results showed that atractylon decreased the MMP, increased ROS levels and inhibited Bcl-2 expression. The activation of Bax and cleaved caspase-3 indicated that atractylon induced apoptosis of HCC cells through the mitochondrial apoptosis pathway. The results also showed that atractylon inhibited the migration and invasion of HCC cells by inhibiting the EMT process and downregulating the expression of matrix metalloproteinases-2 and -9, and also inhibited the growth of HCC cells. Furthermore, it has an inhibitory effect on the EMT process in vivo (109). After atractylon treatment, the proliferation ability of hepatoblastoma cells decreased, and the apoptosis rate increased. The invasion and migration abilities of HepG2 cells were significantly decreased. In addition, atractylon was observed to regulate the expression of thymopoietin-antisense RNA 1 and CCDC18 antisense RNA 1 and inhibit the invasion and migration of liver cancer cells in vitro (110).

Ar-turmerone

Ar-turmerone is one of the active components of Curcuma longa, and ar-turmerone induces apoptosis in HepG2 cells through ROS-mediated activation of ERK and c-Jun N-terminal kinase (JNK) and triggering endogenous and exogenous caspase activation, leading to apoptosis (111).

Other types of sesquiterpenes

Thapsigargin

Guaiane-type sesquiterpenoids are an important class of natural products in nature, and hundreds of guaiane-type sesquiterpenoids have been isolated and identified (112). Guaiane-type sesquiterpenoids belong to the bicyclic sesquiterpenes. The basic mother nucleus is formed by three isoprene units, and generally has a 4,10-dimethyl-7-isopropyl group substitution. Due to the different position of side chains, there are also other types of sesquiterpenes, including pseudoguaiane, patchoulane, carotane, lactarane and daucane (113). Thapsigargin, a guaiacan-type sesquicolide isolated from Thapsia garganica, is an irreversible ER calcium ATPase inhibitor (114), which inhibits sarcoplasmic reticulum calcium pumps (SERCA-ATPase) in human HCC cells. Depleting the intracellular Ca2+ pool induces apoptosis. The X-ray structure of the thapsigargin-SERCA complex provides a basis for understanding the structural conformation of the complex, as well as the surrounding environment of the binding site. It also provides detailed information for the design of targeted prodrugs with thapsigargin as the active ingredient (115). Thapsagargin (G202) has completed phase II clinical trials for the treatment of glioblastoma multiforme and HCC, and is expected to enter the market in the near future (116,117).

(2S,7R,10S)-3-hydroxypseudotigerone-11-O-β-D-glucopyranoside

2S,7R,10S)-3-hydroxypseudotigerone-11-O-β-D-glucopyranoside is an eucalanes type sesquiterpene. It's one of the main chemical constituents of A. lancca (Thunb.) DC (118-120), which had obvious protective effects on HepG2 cells induced by N-acetyl-p-aminophenol at a concentration of 10 μM. The cell survival rate was 34.6%, which is higher than that with bicyclol-positive drugs, indicating that it exhibits a strong hepatoprotective effect (121).

Hinesol

Hinesol is a vanilloid type sesquiterpene, which has been extracted from Atractylis lancea, Atractylodes chinensis, Atractylodes japonica and Atractylodes rhizome (106,122,123); it was observed to inhibit cell proliferation and induce cell apoptosis by arresting the cell cycle in G1 phase of SMMC-7721 and LM3 cells. The mechanism is related to the inhibition of the phosphorylation of MAPK and ERK, and the downregulation of NF-κB p65 and phosphorylated p65 in the nucleus (124).

Curcumenol

Curcuma zedoary, traditionally due to its wide range of plant components, has been reported to have numerous biological activities and is used for many therapeutic effects (125). Curcumenol, an oxidized guaiacan-type sesquiterpene, has obvious anti-tumor, liver cancer inhibition, liver protection and anti-inflammatory effects (126). Aberrant expression of microRNAs (miRs) in HCC can regulate the occurrence and development of HCC (127-130). Previous studies have shown that curcumenol can inhibit the expression of oncogene miR-2l to exert anti-liver cancer effects (131-134). It can inhibit cell proliferation and lead to a significant increase in the apoptotic ratio by regulating the DJ-1 (Parkinsonism-associated deglycase gene encoding a member of the peptidase C56 family of proteins), phosphatase and tensin homolog and PI3K/AKT signal transduction pathways. The drug effect of curcumenol depends on the action time and dosage (135).

Zerumbone

As a representative of humulane sesquiterpenes, zerumbone shows good anti-tumor activity, which is related to the induction of cancer cell apoptosis and anti-proliferative effects (136). It has been shown to inhibit HCC cell proliferation by inducing apoptosis and thus G2/M cell-cycle arrest through inhibition of the PI3K/AKT/mTOR and STAT3 signaling pathways (137), and also by significantly reducing the expression of matrix metalloproteinase-9, VEGF and VEGF receptor proteins in a dose-dependent manner. Inhibition of the proliferation and migration of the HepG2 cell line has been observed (138). Gingerone can significantly increase the apoptosis of HepG2 cells in a certain period of time, and this apoptosis is achieved by regulating the ratio of Bax/Bcl-2 (139-141).

Artemeriopodin G7

Artemisia is one of the largest genera in the Asteraceae family, usually represented by 500 species of small herbs and shrubs (142,143). It is widely distributed in the Northern temperate zone of Asia, Europe and North America (144). Numerous artemisia species (e.g., Artemisia annua, Artemisia atrovirens, Capillary artemisia, Artemisia mongolica and Artemisia nilagirica) have been used as traditional medicines to treat a variety of diseases (145), such as malaria, dysmenorrhea, amenorrhea, hepatitis, inflammation, bruising, jaundice, bleeding and cancer (27,146). Artemeriopodin G7, extracted from Artemisia australis, can inhibit the migration and invasion of HepG2 cells and induce apoptosis. G2/M cell-cycle arrest was induced by downregulation of CDC2 and p-CDC2 levels. In addition, artemeriopodin G7 targeted platelet-derived growth factor receptor A and affected the AKT/STAT signaling pathway (147).

Cryptomeridiol

Cryptomeridiol, a naturally occurring sesquiterpene derivative isolated from traditional Chinese medicine plant Magnolia officinalis, was effective against HCC by exacerbating the pre-activated unfolded protein response and activating the silent nerve growth factor-induced gene B NGFI-B. Mechanistically, Nur77 is induced to sense the inositol-requiring enzyme 1 α/apoptosis signal-regulating kinase 1/JNK signal and transduce to mitochondria, resulting in loss of MMPmitochondrial membrane potential. Cryptomeridiol-induced heightened ER stress and mitochondrial dysfunction resulted in increased cytotoxic products of ROS. The in vivo anti-HCC activity of cryptomeridiol was superior to that of sorafenib, which is currently used to treat advanced HCC. Identification of Nur77 as a molecular target of cryptomeridiol provides a basis for further development of improved anti-HCC drugs (148).

Furanodiene

Furanodiene is a pure compound isolated from Curcuma zedoary. Furanodiene inhibits HepG2 cell growth by causing cell-cycle arrest at G2/M and inducing apoptosis. The furanodiene-mediated mitochondrial caspase apoptosis pathway also involves the activation of p38 and the inhibition of ERK and MAPK signaling (149).

Hirsutanol A

Hirsutanol A is a novel sesquiterpenoid isolated from the endophyte of Sarcophyton tortuosum, a soft coral in the South China sea. The autophagic death of hepatoma carcinoma cells is induced by the activation of ROS (150,151).

Elemene

Elemene is also extracted from Curcuma zedoary as a non-cytotoxic antitumor agent with few side effects, but may inhibit tumor cell proliferation, induce apoptosis and differentiation, eliminate tumor cells, reverse multidrug resistance and inhibit tumor metastasis, particularly in HCC (152-154). Elemene induced apoptosis, inhibited the cell cycle and reversed GSH S-transferase P1 methylation in QGY7703 cells (155).

β-elemene

β-elemene has been shown to have anti-cancer effects on a variety of tumor diseases, including liver cancer, by inhibiting tumor-cell growth or promoting apoptotic cell death. c-Met is a tyrosine kinase receptor, which is widely found to be overexpressed in tumor tissues and involved in cell proliferation, migration, invasion and survival. Downregulation of c-Met expression by β-elemene induced growth inhibition in mouse hepatoma cells (156).

Sesquiterpenoids with an unspecified mechanism of action but an anti-liver cancer effect

One new guaiane-type sesquiterpenoid-Acorusin E, has been isolated from the rhizomes of Acorus tatarinowii. In vitro cytotoxicity was evaluated in liver cancer cells (SMMC-7721 and HepG2 cells) and showed moderate cytotoxicity with IC50 values of 2.11-7.99 μmol (157).

Senecio is an important genus in Asteraceae, with >200 species in China (158), most of which are widely used in folk medicine due to their potent biological activity. Senedensiscin G, which was isolated from Senedensiscin, showed a broad spectrum of inhibitory activity against SMMC-7721 cells (159).

The roots of Scorzonera divaricata have antipyretic and detoxicant activities and are used in traditional medicine to treat toxic ulcers and malignant gastric tumors (160). Sulfoscorzonin E isolated from the aboveground part of Scorzonera divaricata exhibited moderate cytotoxic activity against hepatoma HepG2 cells and possessed strong 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl free radical scavenging abilities (161).

Artemongolins A-K (nos. 1-11), undescribed sesquiterpenoid dimers isolated from Artemisia mongolica, comprise a rare 5/7/5/5/10 hexocyclic system; their structures were unambiguously elucidated through comprehensive spectroscopic analyses, encompassing high-resolution electrospray ionization mass spectrometry for precise molecular formula determination, infrared spectroscopy to identify functional groups, one-dimensional nuclear magnetic resonance (proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, distortionless enhancement by polarization transfer) and two-dimensional nuclear magnetic resonance (correlation spectroscopy, heteronuclear single quantum coherence, heteronuclear multiple-bond correlation, rotating-frame Overhauser effect spectroscopy) experiments for detailed structural connectivity and stereochemical assignment, and electron capture detector calculations using the time-dependent density functional theory to establish absolute configurations. Evaluation of the anti-HCC activity of three human HCC cell lines showed that Artemongolin E had the highest activity (162).

To date, 14 known compounds (nos. 12-25) and Artemyriantholides A-K (nos. 1-11) have been isolated from Artemisia lactiflora. All compounds were chemically characterized as bluish sesquiterpene dimers. The anti-liver cancer assay showed that the 11 compounds had obvious inhibitory effects on HepG2 and Huh7 cells with IC50 values of 7.9-67.1 μM. Artemyriantholides E and H showed good inhibitory activity on HCC. A computational prediction model suggested that the target of Artemyriantholides is mitogen-activated protein kinase kinase 2 (MAP2K2) (163).

At the concentration of 200 μg/ml, the inhibitory effect of ethanol extract of artemisia sacrorum on HepG2 cells was 65.5%, and the inhibitory effect on Huh7 cells was 28.1%, the inhibitory effect of ethyl acetate extract on HepG2 cells was 93.5%, and the inhibitory effect on Huh7 cells was 82.0%. Artemisacrolide B was prominent in three HCC cell lines, with IC50 of 21.9 μM (HepG2), 9.0 μM (Huh7) and 16.9 μM (SK-Hep-1), respectively (164).

Guaiacolide dimers are a unique class of natural products with anticancer activity, but their low content in plants limits in-depth pharmacological studies. Lavandiolide I, a guaiacolide dimer isolated from Artemisia, showed potent anti-HCC activity against the HepG2, Huh7 and SK-Hep-1 cell lines. To explore more active oligomers, 33 derivatives of Lavandiolide I were designed, synthesized and evaluated for their inhibitory activity against human hepatoma cells. Of these derivatives, 10 were more active than Lavandolide I and Sorafenib against all three cell lines. Among them, derivatives 25, 27 and 33 have 1.2-5.8 times higher anti-liver cancer activity than Lavandolide I, and have lower toxicity and better safety against human liver cells (THLE-2), with selection indices between 1.3 and 3.4, while Lavandolide I is more toxic to THLE-2 cells (165).

Mechanism of action of compounds

The first mechanism is through the regulation of the MAPK pathway, which includes stress-activated protein kinase/JNK, ERK and MAPK14 (p38-MAPK) (166). In HCC tissues, activated ERK in turn induces the expression of multiple genes, activates NF-κB and phosphorylates cellular transcription factor-1, promotes cell transition from G1 phase to S phase (167,168), and thus promotes the proliferation of HCC cells. Activated ERK can also upregulate the expression of genes including hypoxia-inducible factor-1α and VEGF-α, and promote the glycolysis process and angiogenesis of HCC. The use of ERK inhibitors can reduce the expression of ERK, resulting in slow cell proliferation and cell apoptosis (169,170). For instance, the furanodiene-mediated mitochondrial caspase apoptosis pathway also involves the activation of p38 and the inhibition of ERK and MAPK signaling.

The second regulatory pathway is inhibition of the PI3K/AKT/mTOR pathway. PI3K can promote the production of phosphatidylinositol-3,4,5-triphosphate, thereby promoting the phosphorylation of AKT and further activating the serine/threonine protein kinase mTOR, promoting protein synthesis and the growth and invasion of liver cancer cells (170,172). For instance, dimethylaminomicheliolide inactivates the PI3K/AKT pathway, leading to ROS production, thereby regulating dimethylaminomicheliolide-induced apoptosis.

As one of the important transcriptional regulators, the third regulatory pathway NF-κB can exert biological effects by regulating the transcriptional expression of a variety of genes. NF-κB has a key role in inflammatory response and tumor development, and plays an important regulatory role in the progression of liver injury, liver fibrosis and HCC (173). In neutrophil-driven HCC, the NF-κB gene can exert negative regulatory effects on the chemokine network in neutrophils. However, NF-κB gene knockout can promote the occurrence of liver cancer (174). For instance, deoxyelephantopin can reduce the phosphorylation of IκB-α to inhibit the translocation of constitutive and inducible NF-κB to the nucleus, and exert its anti-cancer effect through oxidative stress.

The fourth regulatory pathway is the JAK2/STAT3 pathway. The activation of the JAK2/STAT3 pathway is a common mechanism leading to the occurrence of liver cancer, and upregulation of STAT3 is often found in HCC (113). The expression of STAT3, as a driver, plays a key role in the occurrence, progression, metastasis and immunosuppression of HCC, and is associated with poor prognosis (175). For instance, germacarone can also induce apoptosis of HepG2 cells by reducing the expression of STAT3 and JAK2 signaling pathway components.

The last regulatory pathway is induction of mitochondrial dysfunction, the key role of mitochondria in ROS production and apoptotic signaling in tumor cells. Structural and functional differences between mitochondria in normal cells and cancer cells, result in cancer cells are more susceptible to oxidative stress compared to normal cells (176). For instance, atractylon showed that decreased the MMP, increased ROS levels and inhibited Bcl-2 expression. The activation of Bax and cleaved caspase-3 indicated that atractylon induced apoptosis of HCC cells through the mitochondrial apoptosis pathway.

The α- and β-unsaturated carbonyl and α-methylene lactone groups and the conjugated aldehyde groups in sesquiterpene lactones are considered to be reactive partial structures (25,177). Both its cytotoxic and anti-inflammatory properties are partially mediated by α,β-unsaturated carbonyl functions, such as cyclopentenone and α-methylene γ-lactone (178). For instance, when cancer cells were treated with parthenolide, the ROS in tumor cells were increased due to a decrease in the cysteine group of the antioxidant non-protein molecule GSH.

Applications of sesquiterpenes

Given the high cancer-related mortality and the severe side effects of radiotherapy and chemotherapy treatments, researchers and scientists have made great efforts to extract new natural products from plants, microorganisms and other organisms to evaluate their anticancer activity and explore their mechanisms of action, as they are considered to have fewer toxic side effects compared to traditional therapies such as chemotherapy. These efforts have led to the development of anticancer drugs and the introduction of natural products into clinical applications. In 1994, elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration. The drug has been on the market and has become a national second-class anticancer drug with Chinese intellectual property rights. It is used to treat various diseases and bone metastasis. It features affinity for and targeting of tumor cells, as well as sustained release, stability and safety (179). Liposomal elemene is a non-cytotoxic antineoplastic agent with a high content of anticancer active ingredients (85% β-elemene) and is also called a 'green therapy' for cancer treatment. In the clinic, elemene liposome can be used alone or in combination with chemoradiotherapy, or before and after surgery (180). After 20 years of clinical research, elemene liposomes can inhibit a variety of cancer cells through multiple targets and can improve immune function. In particular, it has obvious advantages in improving the quality of life of patients, prolonging survival time, resisting metastasis and recurrence, and reversing multi-drug resistance. At present, rimantagliene injection and oral emulsion have entered the 'National Medical Insurance Drug List' and are used in >3,000 hospitals in China, reaching >700,000 cancer patients, including patients in Southeast Asia, Hong Kong, Japan, South Korea, Europe and the United States (181). However, it can cause serious adverse reactions, such as phlebitis after intravenous injection. To date, various new delivery systems, including solid lipid nanoparticles (NPs) (SLN), nanostructured lipid carriers, long-circulating liposomes, active-targeting SLN, drug-loaded liposomes and microemulsions, self-emulsified drug delivery systems and active-targeting microemulsions, have been developed. Already being actively developed, these systems have contributed to numerous advances in elemene (182).

The development of drug resistance and dose-related toxicity of natural products are the main disadvantages of chemotherapeutic drugs in cancer treatment. Therefore, combination therapy has become a feasible way to improve the efficacy and reduce systemic toxicity of natural products. Although artemisinin is the first choice for anti-malarial drugs, its derivatives have shown remarkable efficacy in the treatment of laryngeal cancer, uveal melanoma and pituitary macroadenoma, and are in phase I to II clinical trials for the treatment of lupus nephritis and diseases such as breast cancer, colon cancer and non-small cell lung cancer. In the treatment of HCC, artesunate, a derivative of artemisinin, can be used to sensitize sorafenib and play a synergistic anti-tumor effect. Because artesunate is well tolerated and affordable, the combination of artesunate and sorafenib can benefit most patients with HCC. In addition, this combination therapy could reduce the potential toxicity of sorafenib by reducing its effective dose (183,184).

Numerous synthetic and herbal medicines have poor oral bioavailability due to their low water solubility or inability to cross biofilms, resulting in poor dissolution in biological fluids and poor therapeutic efficacy. A growing number of reports have highlighted the promise of phosphatidyl-based formulations as effective drug delivery systems for natural bioactive ingredients. Lipid NPs loaded with artemisinin provide a promising approach for HCC treatment, harnessing the respective advantages of artemisinin and lipid NP-based delivery systems (185). Encapsulation of artemisinin in lipid NPs significantly reduced its systemic toxicity. By facilitating targeted drug delivery specifically to the tumor site, artemisinin's cytotoxic effects on healthy tissues can be minimized. This targeted approach reduces the common side effects of traditional chemotherapy, such as gastrointestinal discomfort, liver toxicity and bone marrow suppression. In addition, the use of biocompatible and biodegradable lipids in the formulation of NPs further contributes to the reduction of toxicity. Another study aimed to investigate the liver targeting and anti-HCC effects of artesunate (ART)-loaded, glycyrrhetinic acid (GA)-modified polyethylene glycol (PEG)-poly(lactic-acetic acid) (PLGA) (ART/GA-PEG-PLGA) NPs. ART/GA-PEG-PLGA NPs have pro-apoptotic effects on HepG2 cells, which are mainly achieved by inducing high levels of ROS, reducing MMP and inducing cell cycle arrest. Furthermore, ART/GA-PEG-PLGA NPs induced the endogenous apoptotic pathway in HepG2 cells by upregulating the activity of cleaved caspase-3/7 and the levels of cleaved PARP and phosphorylated p38-MAPK. In addition, ART/GA-PEG-PLGA NPs accumulated more in the liver and had a longer mean retention time, resulting in improved bioavailability. Finally, ART/GA-PEG-PLGA NPs facilitated the targeted distribution of ART in the liver, prolonged the retention time of ART and enhanced its anti-tumor effect in vivo (183).

Discussion

So far, a variety of sesquiterpenes have been found in numerous traditional Chinese medicine and plants, such as the Asteraceae, Gentianaceae, Zingiberaceae, Umbelliferaceae, Olivaceae, Magnoliaceae and Valeriaceae. Previous studies have shown that sesquiterpenes exhibit potential therapeutic effects on anti-tumor, anti-inflammatory, anti-bacterial and anti-cardiovascular diseases, and more new components and physiological activities need to be explored. In the present article, several types of sesquiterpenes were reviewed, revealing that the biological activity of sesquiterpene alcohols was not as good as that of sesquiterpene ketones and sesquiterpene lactones. In the future, compounds with the structure of sesquiterpene alcohols can be modified to strengthen the structure-activity relationship.

A variety of natural substances can inhibit liver cancer by causing growth arrest in cancer cells, inducing apoptosis and inhibiting metastasis. Its regulatory mechanisms mainly include the MAPK signaling pathway, PI3K/Akt/mTOR signaling pathway, NF-κB signaling pathway, JAK2/STAT3 signaling pathway and mitochondrial pathway. For instance, Hinesol has a certain inhibitory effect on the MAPK and NF-κB signaling pathways, and NF-κB is one of the downstream components of the ERK/MAPK signaling pathway. The activation of MAPK can promote the dual phosphorylation and degradation of IκB-α. The crosstalk between the MAPK signaling pathway and the NF-κB pathway plays a crucial role in regulating cell fate. For instance, JNK and p38-MAPK in the MAPK family can activate NF-κB under certain conditions, thereby cooperating to regulate cell survival and death; on the other hand, NF-κB can also affect MAPK activity through a feedback mechanism. The complexity of this interaction allows the two signaling pathways to have different effects on apoptosis under different physiological and pathological conditions. For instance, in the mechanistic pathway of artesunate, AKT can indirectly affect STAT3 activity by phosphorylating a variety of signaling molecules. AKT can phosphorylate and inhibit glycogen synthase kinase 3 (GSK-3), and inhibition of GSK-3 may lead to phosphorylation and activation of STAT3 (187). mTORC1 can affect STAT3 expression and activity by regulating protein synthesis. mTORC1 activation can promote the synthesis of ribosomal proteins and translation initiation factors, which may increase STAT3 expression and phosphorylation. The PI3K/AKT/mTOR signaling pathway is regulated by multiple negative feedback signals that may also affect STAT3 phosphorylation and activity. By inhibiting the proliferation, invasion and differentiation of liver cancer cells and delaying the expression of related factors, it interferes with multiple signal transduction, so as to achieve the purpose of treating liver cancer.

The fatal issues of sorafenib and cisplatin are their drug resistance and severe toxicity, and natural products are considered as a safe and effective alternative for cancer treatment (188), so the chemopreventive concept of plant-derived natural products is becoming increasingly important. The use of natural product monomers from inception to late combination and encapsulation in lipid nanoparticles minimizes toxic effects by facilitating specific, targeted delivery to the tumor site.

Conclusion

To date, numerous studies on sesquiterpenes from the same source have been published, but there is a lack of certain studies on the different effects of sesquiterpenes from different sources. The different or identical efficacy of compounds from various sources can be investigated in the future. Furthermore, numerous studies on the activity of sesquiterpenes are only limited to in vitro tests and animal studies, and further studies are needed to evaluate the in vivo efficacy, mechanism of action, structure-activity relationship and clinical application of these compounds, so as to provide a reasonable and reliable scientific basis for the development of a new generation of safe and effective natural small molecular compounds and promote their clinical application.

Availability of data and materials

Not applicable.

Authors' contributions

YL and JM conceived and designed the study. YL, JM and XD carried out the analysis and wrote the manuscript. All authors have read and agreed to the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

This research was funded by the Chongqing Municipal Education Commission Youth Project (grant no. KJQN202402816) and Chongqing Natural Science Foundation General Project (grant no. 2023NSCQ-MSX1632).

References