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.

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).

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 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 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 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).

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, 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, 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 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 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 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).

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).

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 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).

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 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 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-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).

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 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.

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).

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).

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).

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).

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).

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 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 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).