Alkaloids

Alkaloids are cyclic compounds containing one or more basic nitrogen atoms, making them unique and valuable in medicine. They are classified based on their chemical structure and the plant source from which they are derived. For instance, vinblastine, extracted from Vinca rosea (Apocynaceae family), is classified as an indole alkaloid. It, along with its analogue vincristine, exhibits anticancer activity by inhibiting microtubule polymerization [50]. Another class, proto-alkaloids, consists of plant metabolites derived from aromatic amino acids such as tryptophan, tyrosine, or phenylalanine. An example is colchicine, which is derived from Colchicum autumnale and inhibits cancer progression by disrupting the cytoskeleton of tumor cells, thereby reducing tumor burden in HCC [51]. Camptothecin, a pyrroloquinoline alkaloid extracted from the plant Camptotheca acuminata, exhibits antioxidant properties by decreasing the expression of the Nrf2 protein in an HCC mouse model [52]. Moreover, some alkaloids can modulate immune responses, enhancing the immune system’s ability to recognize and eliminate malignant cells.

Flavanoids

Flavonoids are secondary metabolites classified as polyphenolic compounds, abundantly present in fruits, vegetables, tea, and medicinal plants. They are characterized by aromatic rings with specific degrees of hydroxylation and various substituents that distinguish each flavonoid [53]. These compounds have attracted significant attention due to their ability to modulate signaling pathways involved in tumor development, progression, angiogenesis, and metastasis. Quercetin, found in high concentrations in various berries, onions, apples, and red wine, inhibits the proliferation of liver cancer cells by reducing inflammation and inducing cell cycle arrest [54]. Apigenin, extracted from Petroselinum crispum (parsley), demonstrates antimetastatic potential in an in vivo HCC model by altering miRNA expression and inducing apoptosis [55]. Luteolin, a flavonoid mainly found in broccoli, pepper, thyme, and celery, exhibits anticancer activity in vitro HCC models by modulating the expression of the p53 protein [56]. Genistein, derived from dyer’s broom (Genista tinctoria), reverses the EMT markers and inhibits cancer cells’ migration and invasion [57].

Terpenoids

Terpenoids are among the most diverse groups of phytochemicals, derived from terpenes composed of repeating isoprene units that form characteristic carbon skeletons. Based on the number of isoprene units, terpenes are classified into several groups, including monoterpenoids, sesquiterpenoids, diterpenoids, and triterpenoids [58]. Tanshinone I, a diterpenoid found in lavender, peppermint, cherries, celery seeds, and lemongrass, exhibits anticancer activity by inducing apoptosis and inhibiting p53-mediated autophagy in the HepG2 cell line model [59]. Parthenolide, a sesquiterpene lactone derived from Tanacetum parthenium (feverfew), exerts anticancer effects by modulating the immune system, reducing inflammation, and interfering with signaling pathways involved in the inflammatory response [60]. Ursolic acid, a triterpenoid found in apple peel, rosemary, thyme, oregano, and lavender, functions as an antioxidant and anti-inflammatory agent, and also reverses sorafenib resistance in HCC cells in an in vitro model [61]. Furthermore, saponins, a class of triterpenoids, exhibit anticancer properties by inducing apoptosis and blocking the β-catenin signaling pathway in the HCC mouse model [62]. Additionally, various terpenoids have been shown to inhibit angiogenesis, migration, and invasion of cancer cells, further highlighting their potential in cancer therapy.

Polyphenols

Polyphenols have shown strong potential to inhibit cancer progression in both in vitro and in vivo models. These compounds are classified based on their structure and function. For example, flavonoids, found in the root bark of plant species such as Ramulus mori (Moraceae family) and Sophora flavescens (Leguminosae family), act as antioxidants and anti-inflammatory agents, and inhibit the proliferation of HCC cells in vitro by modulating the ERK signaling pathway [63]. Stilbenes, another class of polyphenols found in red grapes and peanuts, exhibit anticancer and antimetastatic properties in vitro HCC models by inducing autophagy [64]. Phenolic acids, primarily present in fruits (especially berries), vegetables, cereals, legumes, and beverages such as coffee and wine, demonstrate anticancer activity by inducing apoptosis and modulating the TME in both in vivo and in vitro [65]. Lignans combat HCC through multiple mechanisms, including the induction of apoptosis and the inhibition of angiogenesis. Sesame and flax seeds are among the most concentrated dietary sources of lignans [66].

Curcuma longa

Curcumin, a potent polyphenol extracted from Curcuma longa of the Zingiberaceae family, is widely found in the southeastern and southern regions of tropical Asia. It has been a key component of Ayurvedic and traditional Chinese medicine for centuries [92]. It has gained attention for its anti-proliferative, antimetastatic, and anti-inflammatory properties, as well as its ability to regulate multiple signaling pathways, making it a promising anticancer agent. A study reported that curcumin modulates the expression of cell adhesion markers—E-cadherin, N-cadherin, vimentin, and fibronectin, thereby regulating EMT through the TGF-β1 (transforming growth factor-β1) pathway and inhibiting HIF-1α in HepG2 cells, ultimately reducing tumor invasion and migration [93].

Curcumin acts on multiple molecular targets, including TGF-β, toll-like receptors (TLRs), and matrix metalloproteinases (MMPs), and also inhibits HCV replication, highlighting its antiviral potential [94, 95]. Curcumin inhibits cancer cell proliferation by mechanisms such as suppressing CDK2 activity in colon cancer [96]. In vitro studies have further demonstrated that curcumin induces cell cycle arrest at the S phase by downregulating cyclin A1 and promotes apoptosis by upregulating pro-apoptotic proteins, including Bax and caspase-3 [97]. It further suppresses cancer progression by blocking key signaling pathways such as NF-κB and Wnt, which are involved in cell proliferation and migration [98]. The combination of curcumin with metformin enhances therapeutic efficacy compared to curcumin alone by targeting the PI3K/Akt/mTOR/NF-κB and EGFR/STAT3 pathways, thereby suppressing angiogenesis and metastasis [74]. However, curcumin faces limitations such as poor absorption, rapid metabolism, and high clearance, with most of it excreted in unmetabolized sulfated or glucuronidated forms. A study using pH-sensitive nanoparticles co-loaded with doxorubicin and curcumin demonstrated improved drug delivery and enhanced inhibition of HCC proliferation [99].

Panax ginseng

The Araliaceae family, particularly the Panax genus, produces ginsenosides—also known as gintonin—a group of triterpenoid saponins derived from ginseng with notable anti-HCC properties [100]. Ginseng, primarily found in China and India, contains various ginsenoside subtypes, including ocotillol-type pseudo-ginsenosides, oleanane, protopanaxatriol (PPT), and protopanaxadiol (PPD). Among these, PPD significantly inhibits HCC cell migration and invasion. A recent study reported that PPD reduces STAT3 phosphorylation, thereby preventing its dimerization and nuclear translocation, leading to downregulation of TWIST1 expression. This effect reverses EMT in HCC by increasing E-cadherin levels and decreasing N-cadherin levels [101]. Another PPD derivative, ginsenoside Rh2, inhibits autophagy and reduces β-catenin levels in HCC cells in a dose-dependent manner [102]. A modified form, 20(S)-PPD, induces apoptosis by suppressing the PI3K/Akt signaling pathway, further inhibiting HCC proliferation [100, 103]. Additionally, ginsenoside Rg3 has been shown to reduce long non-coding RNA (lncRNA) expression and inhibit the PI3K/Akt pathway in vitro studies, resulting in reduced HCC cell migration [104].

Glycyrrhiza glabra

Glycyrrhiza glabra (liquorice), a medicinal plant from the Leguminosae family, is widely used in Ayurvedic medicine and primarily found in Central Asia and China [105]. Its root extract contains glycyrrhizin, a sweet-tasting tetracyclic triterpenoid saponin, commonly used as a flavouring agent in food and medicine. Liquorice is rich in bioactive compounds, including glycyrrhizin, glycyrrhetinic acid (GA), liquiritigenin, isoliquiritigenin, licochalcone A, licopyrano-coumarin, and glabrocoumarin. Among these, glycyrrhizin and GA have shown significant anticancer and antimetastatic potential. Glycyrrhizin is metabolized into GA by gut microbiota, which is responsible for its therapeutic effects [106]. GA (also known as enoxolone) exhibits anti-inflammatory, anticancer, and pro-apoptotic activities. It suppresses HCC proliferation by inhibiting the JNK1 pathway, which is associated with malignant transformation, and reduces the self-renewal capacity of HSCs [107]. In combination with sorafenib, GA enhances anticancer efficacy. It also inhibits cell migration and metastasis by targeting the EGFR, ERK, and Akt signaling pathways [108]. GA binds specifically to a receptor on the sinusoidal surface of hepatocytes (GA receptor), enabling its use in targeted drug delivery. For instance, GA has been conjugated with 5-fluorouracil (5-FU) via an alkyl side chain, resulting in increased ROS (reactive oxygen species) production and enhanced apoptosis [109]. Additionally, licochalcone A, a compound from Glycyrrhiza inflata, shows synergistic effects with sorafenib by blocking the MKK-4/JNK signaling pathway, thereby inhibiting HCC metastasis [76].

Picrorhiza kurroa

Picrorhiza kurroa (kutki) is a medicinal plant native to high-altitude regions (3,000–5,500 meters) of the Himalayas, India, Pakistan, Nepal, and Tibet. Belonging to the Plantaginaceae family, it includes two species: P. kurroa Royle ex Benth and P. scrophulariiflora Pennell [110, 111]. Valued in Ayurvedic medicine, the plant’s roots and rhizomes produce two primary crystalline compounds—picroline and kutkin—which contain various bioactive phytochemicals, including glycosides, iridoids, alkaloids, and terpenes. Among these, iridoids are the major class, featuring compounds such as picroside I–V, verminoside, catalpol, veronicoside, specioside, 6-feruloylcatalpol, pikuroside, and aucubin [112]. Picroside II has demonstrated antimetastatic and anti-angiogenic effects in both cellular and animal models [113]. It reduces inflammation by lowering TNF-α, IL-1β, and IL-6 levels and inhibiting NF-κB signaling in rat lung tissue [114]. In HCC models, picroside II targets glycosylphosphatidylinositol (GPI)-anchored signaling, suppressing cell proliferation and migration. However, further studies are needed to fully understand its role in inhibiting tumor cell migration [70].

Silybum marianum

Silymarin is a bioactive extract derived from Milk thistle (Silybum marianum), a medicinal plant known for its distinctive milky-white-veined leaves. It remains stable in acidic environments but degrades in alkaline conditions, making it effective in the acidic microenvironment of tumors. Silymarin comprises several active compounds, including silybin (or silibinin), isosilibinin, silydianin, silychristin, isosilychristin, and taxifolin. Among these, silybin is the most prominent for its anti-cancer properties, demonstrating antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, antimetastatic, and anti-angiogenic effects [115]. Silybin shows enhanced therapeutic efficacy when combined with other agents. For example, in combination with doxorubicin, it induces cell cycle arrest at the G2-M phase by regulating the cdc25C-cyclin B1-cdc2 pathway and promotes apoptosis [116]. When paired with sorafenib, silibinin effectively suppresses the self-renewal capacity of cancer stem cells by downregulating stemness-related markers such as Nanog and Klf4 [117]. Additionally, silybin inhibits tumor progression in HCC by downregulating MMPs and modulating key signaling pathways, including the ERK1/2 cascade, Slit-2/Robo-1, and by suppressing PD-L1 expression, thereby enhancing T-cell activation [118, 119].

Allium sativum L.

Garlic (Allium sativum L.), a member of the Liliaceae family, is a herbaceous plant widely cultivated in India, Central Asia, and surrounding regions. Known for its pungent aroma and flavor, garlic is rich in sulfur-containing phytochemicals that contribute to its extensive nutritional, physiological, and medicinal benefits [120, 121]. Approximately 82% of garlic’s sulfur compounds include allicin, diallyl sulfide (DAS), diallyl trisulfide (DATS), E-/Z-ajoene, and S-allyl cysteine (SAC) sulfoxide. It also contains other organosulfur compounds such as SAC, N-acetylcysteine, and S-allyl mercapto cysteine (SAMC) [121, 122]. Among these, allicin (diallyl thiosulfinate) is the principal bioactive component with significant anticancer activity [123].

Although naturally derived from garlic, allicin is liposoluble and unstable post-synthesis, rapidly converting in vitro into secondary metabolites such as DADS (diallyl disulfide), DATS, SAC, SAMC, and γ-glutamyl-SAC (GSAC), which can also be synthesized artificially [122, 124]. Studies show that allicin induces apoptosis via the p38/MAPK signaling pathway in gastric carcinoma cells [125] and through p53-mediated autophagy in Hep3B cells [85]. Additionally, allicin suppresses telomerase activity, contributing to cancer cell apoptosis and senescence [126, 127]. It also inhibits the NF-κB pathway and modulates inflammatory cytokines by promoting pro-inflammatory signaling and inducing autophagy through TAMs in hepatoma cells [128–130].

Allicin exhibits antimetastatic properties across various cancers. In gastric cancer, it inhibits cell migration by upregulating miR-383-5p and blocking ERBB4/PI3K/Akt signaling, while in cholangiocarcinoma, it suppresses MMP-2 and MMP-9 activity [131, 132]. In breast cancer, it enhances doxorubicin sensitivity by inhibiting the Nrf2/HO-1 pathway and promoting apoptosis [133, 134]. DATS, another allicin metabolite, also shows anticancer activity in HCC. In HepG2 cells, DATS induces apoptosis by activating the AMPK/SIRT1 pathway [135] and disrupts the ubiquitination of APPL1 via inhibition of TRAF6-mediated K63-linked polyubiquitination, leading to the inactivation of STAT3, Akt, and ERK1/2 pathways and suppression of tumor progression [136]. However, these findings are based on in vitro models, and further in vivo studies are necessary to validate DATS’s therapeutic potential in HCC.

Azadirachta indica

Azadirachta indica, commonly known as neem or “The Village Pharmacy”, belongs to the Meliaceae family. Valued in modern medicine as well as traditional systems such as Unani, Ayurveda, and Homeopathy, neem is recognized for its wide range of therapeutic properties. Its bioactive compounds fall into two major categories: isoprenoids and non-isoprenoids. Key constituents include azadirachtin, nimbolide, gedunin, nimbin, nimbidin, quercetin, and limonoids. These compounds contribute to disease prevention by reducing inflammation, inducing apoptosis, inhibiting angiogenesis, modulating immune responses, and providing antioxidant effects. Notably, neem exhibits significant anticancer activity by altering cancer cell behavior, making it a promising agent for cancer therapy [137].

Nimbolide, a potent limonoid derived from neem flowers and leaves, possesses diverse pharmacological properties including antimalarial, antibacterial, antiviral, antioxidant, anti-inflammatory, anti-invasive, neuroprotective, hepatoprotective, and pro-apoptotic effects. It enhances antioxidant defence by increasing the activity of enzymes such as glutathione (GSH) peroxidase, catalase, and superoxide dismutase (SOD) [138, 139]. Nimbolide also regulates lipid metabolism by modulating genes like liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor-γ (PPARγ), and sterol regulatory element-binding protein-1c (SREBP1c) in hepatocytes [140]. In autoimmune hepatitis, nimbolide exerts anti-inflammatory effects by targeting histone deacetylase 3 (HDAC3), thereby reducing the expression of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α [141]. In HCC, nimbolide enhances tight junction integrity by upregulating proteins such as ZO-1 and occludin, thereby preserving membrane polarity and reducing cell migration. Our previous study confirmed these effects, along with its anti-inflammatory properties [142]. However, further investigation is needed to fully elucidate nimbolide’s role in metastasis prevention in HCC.

Furthermore, in prostate cancer, nimbolide downregulates metastasis-associated genes like MMP-9 and ICAM1, reducing cell migration and invasion [143]. In oral cancer, it induces autophagy-dependent apoptosis by inhibiting the PI3K/Akt signaling pathway [144].

Nimbolide also reverses EMT markers in triple-negative breast cancer (TNBC) cells and inhibits the integrin-FAK (ITG-FAK) signaling pathway, affecting actin cytoskeleton remodeling and promoting apoptosis [145]. In pancreatic cancer, combining nimbolide with docetaxel (DTX) enhances DTX sensitivity, suppressing tumor growth and metastasis through inhibition of NF-κB signaling and promotion of apoptosis [146, 147].

Numerous medicinal plants exhibit promising antimetastatic effects in HCC through well-defined molecular mechanisms. Curcumin longa inhibits PI3K/Akt/mTOR/NF-κB pathway and downregulates MMPs-2/9 and VEGF, thereby impeding angiogenesis and invasion. Andrographis paniculata suppresses tumor progression by modulating HMGB1 and MMP-9 expression via upregulation of miR-22-3p. Camptotheca acuminata affects EMT markers by downregulating Nrf2 and N-cadherin while upregulating E-cadherin. Silybum marianum activates the AMPK-DR5 pathway, inhibiting glycolysis and inducing apoptosis. Collectively, these phytochemicals target critical oncogenic processes.