Advances on mechanisms and structural classification of Chinese herbal monomers against hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality. Current therapies face challenges including drug resistance and toxicity. Chinese herbal monomers, characterized by multi-target effects and low toxicity, represent a promising source for anti-HCC drug development. To systematically summarize active Chinese herbal monomers against HCC, classify them by chemical structure, and elaborate their molecular mechanisms. A systematic literature search was initially performed up to December 15, 2025, with an updated search to June 15, 2026. Search terms included combinations of “hepatocellular carcinoma”, “Chinese herbal monomer”, “saponin”, “flavonoid”, “alkaloid”, “terpenoid”, “quinone”, as well as specific compound names and mechanism-related terms such as “apoptosis”, “cell cycle”, “metastasis”, and “drug resistance”. Studies were included if they investigated purified monomers from Chinese herbs with documented anti-HCC activity; reviews, studies on crude extracts without active compound identification, and non-English/Chinese publications were excluded. Data on chemical classification, mechanisms of action, key experimental details (e.g., cell lines, IC₅₀ values, animal models), and signaling pathways were extracted and synthesized narratively by compound class. Chinese herbal monomers exert anti-HCC effects through a multi-dimensional network. They induce various forms of programmed cell death (apoptosis, autophagy, ferroptosis, pyroptosis), inhibit proliferation via cell cycle arrest (G1/S, G2/M), and curb metastasis by suppressing epithelial-mesenchymal transition and invasion-related proteins. They also modulate the tumor microenvironment, reverse multi-drug resistance, and regulate key signaling pathways (phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin, nuclear factor-kappa B, mitogen-activated protein kinases, Wnt/β-catenin). Preliminary structure-activity relationships are observed within compound classes. Chinese herbal monomers demonstrate significant potential as multi-target agents against HCC. However, their clinical translation requires overcoming pharmacokinetic limitations and conducting rigorous clinical validation. Recent advances in drug delivery systems and combination strategies offer promising directions.

Key Words: Hepatocellular carcinoma; Chinese herbal monomers; Flavonoids; Saponins; Apoptosis; Cell cycle arrest; Drug delivery systems; Ferroptosis; Immunomodulation

Core Tip: Hepatocellular carcinoma is a common and deadly liver cancer. This review focuses on active compounds from traditional Chinese herbs, organized by chemical structure. These natural compounds can suppress tumors in multiple ways simultaneously: They induce tumor cell death, block proliferation and metastasis, and modulate the immune microenvironment. By linking chemical structure to biological activity, this review provides a useful guide for developing these compounds into new liver cancer drugs, with an emphasis on recent advances in overcoming translational barriers such as poor bioavailability and lack of clinical evidence.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most prevalent pathological type of primary liver cancer and ranks among the leading causes of cancer-related mortality worldwide[1,2]. Its onset is often insidious, with most patients diagnosed at intermediate or advanced stages, missing the window for curative resection[2]. Currently, systemic treatment has entered an era of combination immunotherapy, with molecular targeted agents (e.g., sorafenib, lenvatinib) and immune checkpoint inhibitors [e.g., programmed cell death-1/programmed cell death-ligand 1 (PD-L1) inhibitors] constituting the backbone of mainstream options[2,3]. However, these regimens commonly encounter challenges including primary or acquired resistance, tumor heterogeneity, and significant toxic side effects, resulting in suboptimal overall survival benefits for patients[4]. Conversely, traditional Chinese medicine (TCM) formulas demonstrate synergistic potential with multi-component, multi-target characteristics in the prevention and treatment of HCC[5]. Therefore, exploring and developing novel anti-HCC drugs with well-defined mechanisms, confirmed efficacy, and superior safety profiles remains a critical scientific challenge in the field.

In the context of HCC, TCM has accumulated extensive practical experience, adhering to the core principles of “holistic concept” and “treatment based on syndrome differentiation”. Modern research increasingly indicates that Chinese herbs and their active components exhibit unique advantages in intervening at multiple stages of HCC progression, particularly by modulating the tumor microenvironment[6]. Among these, Chinese herbal monomers – defined as single, pure compounds extracted, isolated, and identified from Chinese herbs – serve as a crucial bridge connecting the valuable experience of TCM with modern innovative drug research and development due to their well-defined chemical structures and easily interpretable pharmacological actions.

Compared to traditional chemically synthesized drugs, Chinese herbal monomers exhibit a distinctive “multi-target” characteristic in anti-cancer research. They can simultaneously intervene at multiple key signaling nodes during tumor development and progression, such as inducing apoptosis, arresting the cell cycle, inhibiting epithelialmesenchymal transition (EMT) and angiogenesis, and modulating the tumor microenvironment[7]. This mode of synergistic action through multiple pathways may not only lead to superior efficacy but also help overcome the resistance issues often associated with single-target drugs[7]. Moreover, many Chinese herbal monomers are derived from medicinal and edible plants, typically demonstrating lower systemic toxicity, providing an inherent advantage for their safe clinical application[8].

Systematically classifying Chinese herbal monomers based on chemical structure and investigating their structure-activity relationships is an important paradigm in modern TCM research. This approach not only helps clarify the intrinsic patterns linking biological activity to different structural types and identify key pharmacophores but also provides clear scientific guidance for subsequent structural modification and optimization to enhance compound activity, selectivity, and druggability – a paradigm that has been well exemplified in the study of polysaccharides from Chinese herbs[9]. Furthermore, growing attention is being paid to the role of Chinese herbal monomers in regulating epigenetic mechanisms such as microRNA and non-coding RNA networks[10], as well as their interplay with the tumor immune microenvironment[6], offering new research directions in this field.

METHODOLOGY

A systematic literature search was initially performed in PubMed and Web of Science for articles published up to December 15, 2025. During the revision of this manuscript, an updated search was conducted to include articles published up to June 15, 2026. The search strategy combined terms related to hepatocellular carcinoma (“hepatocellular carcinoma” OR “liver cancer” OR “HCC”) with terms for Chinese herbal monomers (“Chinese herbal monomer” OR “Chinese herb” OR “traditional Chinese medicine”) and specific compound classes (“saponin”, “flavonoid”, “alkaloid”, “terpenoid”, “quinone”, “phenolic acid”, “polysaccharide”, etc.). Additional searches were conducted using specific compound names identified in preliminary screening. Reference lists of included studies and relevant reviews were also hand-searched.

CLASSIFICATION AND MECHANISMS OF CHINESE HERBAL MONOMERS

The pharmacological activity of Chinese herbal monomers is closely related to their specific chemical scaffolds. Based on their core structures, monomers with anti-HCC activity can be primarily classified into saponins, flavonoids, alkaloids, terpenoids, quinones, and other categories. This section systematically elaborates on the chemical characteristics and anti-HCC mechanisms of representative monomers from each class, with an emphasis on recent advances from the past five years and critical assessment of the available evidence.

Saponins

Saponins are a class of glycosidic compounds composed of a hydrophobic sapogenin and a hydrophilic sugar chain. Due to their amphiphilic nature, these components easily interact with biomembranes, exhibiting a wide range of biological activities and constituting an important family in anti-HCC research. Recent reviews have comprehensively summarized the anti-tumor mechanisms and structure-activity relationships of triterpenoid saponins[11].

Platycodin D: A triterpenoid saponin with multi-mechanistic anti-HCC activity. Earlier studies demonstrated that platycodin D (PD) induces mitochondria-mediated apoptosis (increased Bax/Bcl-2 ratio, caspase-3/9 activation) and triggers extracellular signal-regulated kinases (ERK)-dependent and c-Jun N-terminal kinase (JNK)-dependent protective autophagy in BEL-7402 cells[12]. More recently, PD was shown to reverse histone deacetylase inhibitor resistance by suppressing ERK1/2-mediated cofilin-1 phosphorylation, with tumor growth inhibition observed at doses of 10-20 mg/kg (i.p.) in a Huh7 xenograft mouse model[13]. Recent pharmacological reviews have confirmed that PD downregulates BIRC5 (survivin) expression in HepG2 and Huh7 cells and highlighted its immunomodulatory potential, though low oral bioavailability remains a translational challenge[14,15]. While the interplay between apoptosis and protective autophagy in orthotopic models remains incompletely defined, these pharmacokinetic limitations must be addressed before clinical translation.

Notoginsenoside Ft1: A dammarane-type triterpenoid saponin. A 2025 study demonstrated that Ft1 inhibits the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in HepG2 and Huh7 cells, inducing both apoptosis and a unique form of lysosome-dependent cell death. RNA-sequencing further revealed that Ft1 downregulates the expression of multiple mitogen-activated protein kinases (MAPK)-associated oncogenes (including KRAS, BRAF, and FOS), suggesting a potential inhibition of MAPK signaling activity[16]. In vivo, Ft1 effectively suppressed tumor growth in a Huh7 xenograft model[16]. A limitation of this study is the exclusive use of Huh7 cells for the in vivo model; confirmation in additional cell lines or patient-derived xenografts (PDX) would strengthen the conclusion.

Tubeimoside I: A triterpenoid saponin whose core anti-HCC mechanism involves inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway through upregulation of tumor necrosis factor alpha-induced protein 3 (TNFAIP3). In vitro (MHCC97-H, SNU-449) and in vivo (subcutaneous xenograft model) studies confirmed that tubeimoside I induces dose-dependent cell growth inhibition and apoptosis, with significant tumor volume reduction observed at doses tested[17]. The TNFAIP3-mediated negative feedback inhibition of NF-κB signaling has been identified as a key anti-HCC mechanism, highlighting its potential therapeutic relevance[18]. However, the study lacks a systematic multi-concentration assessment of TNFAIP3 expression levels, and the potential off-target effects of TNFAIP3 upregulation remain uninvestigated.

Astragaloside IV: A cycloartane-type triterpenoid saponin with multi-dimensional synergistic characteristics. Astragaloside IV induces apoptosis and G1 phase cell cycle arrest in SK-Hep1 and Hep3B cells[19], inhibits HCC progression via transforming growth factor beta (TGF-β)/Smad and Nrf2/HO-1 pathways in a DEN-induced fibrosis-HCC mouse model[20], and reverses cisplatin resistance by suppressing MRP2 in H22 tumor-bearing mice (40 mg/kg i.g.)[21]. While the multi-target effects are well demonstrated, most in vivo data come from subcutaneous or chemically induced models; validation in genetically engineered mouse models or spontaneous HCC models is still absent.

Timosaponin A-III: A steroidal saponin with potent anti-HCC activity. Timosaponin A-III (TAIII) induces mitochondria-dependent apoptosis via activation of caspases and release of cytochrome C, HtrA2/Omi, and Smac/Diablo from mitochondria[22]. In HepG2 cells, TAIII significantly suppresses proliferation and promotes apoptosis in a concentration- and time-dependent manner[23]. TAIII also degrades XIAP via an AMPKα/mTOR-dependent autophagic-lysosomal pathway[22]. In vivo, TAIII significantly suppresses tumor growth in HCC xenograft models without severe hepatic toxicity, and liposomal formulations have been developed for enhanced delivery[24]. However, the translational potential of TAIII is challenged by low oral bioavailability (9.18%) and concerns regarding hepatotoxicity via oxidative stress and bile acid transporter downregulation[25,26].

α-Hederin: A pentacyclic triterpenoid saponin. It inhibits HCC metastasis by targeting the PAF/PTAFR signaling axis, subsequently suppressing downstream signal transducer and activator of transcription 3 (STAT3) and matrix metalloproteinase 2 (MMP-2) expression, as demonstrated in both in vitro and lung metastasis models[27]. The in vivo model used is a tail vein injection metastasis model, which bypasses the initial steps of invasion and intravasation; an orthotopic or spontaneous metastasis model would provide more clinically relevant insights.

Paeoniflorin: This monomer holds unique value in intervening in HCC associated with psychological stress. A 2025 study demonstrated that paeoniflorin targets SRC kinase, blocking norepinephrine-induced activation of hepatic stellate cells and inhibiting malignant crosstalk between neuroendocrine signaling and the tumor microenvironment in a chronic restraint stress-HCC mouse model (50 mg/kg i.g.)[28]. The study elegantly incorporates psychological stress, but does not assess long-term safety or possible interference with standard antidepressants; clinical translation remains distant.

Collectively, saponins exert anti-HCC effects primarily by inducing mitochondria-mediated apoptosis, inhibiting the PI3K/AKT/mTOR and MAPK pathways, and blocking the NF-κB signaling axis. However, the majority of studies rely on a limited panel of HCC cell lines (mainly HepG2 and Huh7) and subcutaneous xenograft models; pharmacokinetic properties and long-term toxicity remain understudied, representing a critical gap for future translational research.

Flavonoids

Flavonoids are characterized by a 2-phenylchromone basic skeleton, widely distributed in the plant kingdom, and renowned for their potent antioxidant, apoptosis-inducing, and cell cycle arrest activities. Recent comprehensive reviews have systematically cataloged the anti-HCC mechanisms of flavonoids derived from Scutellaria baicalensis[29].

Scutellarein: This flavonoid exhibits dual anti-HCC mechanisms in Hep3B cells, inducing extrinsic apoptosis by activating the death receptor pathway (Fas/FasL, caspase-8/3) and inhibiting tumor cell proliferation by arresting the cell cycle at the G2/M phase via downregulation of Cdc25C, CDK1, and cyclin B1[30]. The study is limited to a single cell line and lacks in vivo validation; the clinical relevance of the observed concentrations remains unknown.

Kaempferol: Derived from Alpinia officinarum, kaempferol exerts antiHCC effects by inducing G2/M phase arrest through regulation of the ATM/CHEK2/KNL1 pathway in HCCLM3 and Huh7 cells, and reduces tumor growth in threedimensional tumor spheroid models[31]. A subsequent study demonstrated that the kaempferol glycoside kaempferitrin exhibits antitumor efficacy in an SMMC-7721 xenograft model[32]. Although tumor spheroids mimic key features of human solid tumors, confirmation in conventional in vivo models is needed.

Hydroxygenkwanin: Extracted from the flower buds of Daphne genkwa, its core anti-HCC mechanism involves inducing miR-320a expression, which subsequently inhibits FOXM1 and FOXM1-mediated EMT, thereby curbing tumor proliferation and invasion in HepG2 and Huh7 cells and in mouse xenograft models[33]. A 2020 study further demonstrated that HGK inhibits class I HDAC expression and synergistically enhances the antitumor activity of sorafenib in liver cancer cells[34]. The original study does not specify the HCC cell line used for xenograft establishment, which limits reproducibility of the in vivo findings.

Licochalcone A: As a chalcone flavonoid, its anti-HCC effect is primarily achieved by inducing ferroptosis. In vitro (HepG2, Huh7) and in vivo studies show it induces ferroptosis via the SLC7A11/GPX4 pathway, leading to reactive oxygen species (ROS) accumulation and lipid peroxidation[35]. A 2024 comprehensive review further summarized licochalcone A’s regulation of non-coding RNA in anti-cancer activities, suggesting additional layers of complexity[36].

Baicalein/baicalin/wogonin: Preclinical studies have extensively characterized the anti-HCC mechanisms of baicalein, a major active component from Scutellaria baicalensis[37]. Baicalein induces G0/G1 phase arrest via a β-catenindependent mechanism in Bel-7404 and HepG2 cells, and significantly inhibits tumor growth in mouse xenograft models without obvious adverse effects[37]. Baicalein also suppresses the mitogen-activated protein kinase-ERK signaling pathway and inhibits HCC metastasis by downregulating MMP-2, MMP-9 and urokinase-type plasminogen activator expression in MHCC97H cells (0-30 μM) and in a nude mouse LCI-D20 model (10 mg/kg/day)[38]. Baicalin induces repolarization of tumor-associated macrophages from M2-like to M1-like phenotype via autophagy-associated activation of RelB/p52, and oral administration (50 mg/kg) completely blocks orthotopic growth of implanted HCC[39]. Wogonin suppresses proliferation and invasion, and induces apoptosis of HepG2 and Bel7402 cells through multiple pathways[40]; it also directly suppresses STAT3 phosphorylation, thereby downregulating immunosuppressive molecules and promoting the recruitment of dendritic cells, T cells and NK cells into tumor tissues[41].

Chrysin: This flavonoid exerts antiHCC effects via a “metabolismapoptosis” dual mechanism by targeting HK2, blocking tumor glycolysis while simultaneously inducing mitochondriadependent apoptosis in HCCLM3 cells and xenograft models[42]. The study does not report pharmacokinetic data (e.g., oral bioavailability, halflife) nor measure direct HK2 target occupancy in tumors. Chrysin’s extremely low oral bioavailability (0.003%-0.02%) severely limits clinical utility, spurring recent interest in nanoformulation strategies[43].

Eupafolin: This flavonoid exerts anti-angiogenic effects via a “targeting endothelium-inhibiting secretion” dual pathway, directly inhibiting VEGF/VEGFR2 signaling in HUVECs while also reducing VEGF secretion from HepG2 cells, and reducing microvessel density in xenograft models[44]. The anti-angiogenic effect is well demonstrated, but the study does not assess whether the observed reduction in microvessel density translates into improved overall survival or reduced metastasis.

Hydroxysafflor yellow A: Recent studies demonstrate that hydroxysafflor yellow A exerts potent anti-angiogenic effects in HCC by suppressing p38 MAPK phosphorylation and inhibiting the downstream p38 MAPK/ATF-2 signaling pathway[45]. Additionally, hydroxysafflor yellow A modulates tumor vascularization through intercellular communication and extracellular matrix-receptor interactions[46].

Puerarin: An isoflavone compound that inhibits SMMC-7721 cell proliferation and induces apoptosis via the mitochondria-dependent pathway[47]. Due to its restricted solubility, pharmacokinetic studies have revealed that puerarin has a low bioavailability, which limits its clinical application[48]. Recent advances include nanoformulations (nanoPue) that significantly suppress tumor growth and enhance chemosensitivity in HCC xenograft models via regulating NSUN2 and inhibiting angiogenesis[49], and puerarin has been shown to suppress HCC progression by blocking the PI3K/AKT/mTOR pathway[50].

Icaritin: A prenylflavonoid derivative that modulates the tumor immune microenvironment by enhancing the anti-tumor function of CD8⁺ T cells, inhibiting myeloid-derived suppressor cells, and regulating multiple cytokines[51]. Importantly, icaritin is one of the few compounds that have entered clinical trials for HCC. A recent clinical study demonstrated that transarterial chemoembolization combined with lenvatinib and icaritin significantly improved objective response rate, disease control rate, and progression-free survival compared to transarterial chemoembolization alone in patients with unresectable HCC and poor performance status[52]. A real-world study of 26 HCC patients showed icaritin-based combination therapy achieved a disease control rate of 93.8% and a median overall survival of 10.6 months, with the incidence of grade 3 treatment-related adverse events at 13.9% and no grade 4+ treatment-related adverse events observed[53].

Flavonoids are characterized by their potent ability to induce cell cycle arrest and regulate various forms of programmed cell death. Licochalcone A is a potent inducer of ferroptosis, while chrysin uniquely targets HK2 to inhibit tumor glycolysis. Despite these promising findings, the clinical translation of most flavonoids is hindered by poor bioavailability, and few compounds have advanced to rigorous in vivo efficacy studies using orthotopic or PDX models. Icaritin represents the most clinically advanced flavonoid, but phase III data are still awaited.

Alkaloids

Alkaloids are a class of nitrogen-containing, basic organic compounds with complex and diverse structures, often exhibiting significant cytotoxicity and signaling pathway regulatory effects. Recent reviews on phytochemicals have highlighted the emerging roles of alkaloids in anti-HCC therapy, together with other natural products[54].

Matrine: A quinolizidine alkaloid that exerts anti-HCC effects through multiple mechanisms. In vivo studies in a diethylnitrosamine/2-AAF-induced rat model demonstrated that matrine (0.25-2.5 g/L, intragastric administration) prevents the early development of HCC-like lesions by suppressing Notch1 and Hes1 activation[55]. Matrine also inhibits cancer metastasis by directly targeting MMP-9[56]. Furthermore, pharmacological evidence indirectly supports that matrine regulates tumor-associated coagulation abnormalities by targeting plasminogen, as predicted by molecular docking studies, although direct experimental validation in vivo is still warranted[57].

Aconitine: A diterpenoid alkaloid that specifically inhibits the proliferation of HCC cells (HepG2, Huh7) in a dose-dependent manner (0-100 μg/mL) with relatively low toxicity towards normal hepatocytes (L02). Mechanistically, aconitine induces apoptosis through upregulation of Bax, downregulation of Bcl-2, activation of caspases 3 and 7, and promotion of ROS-mediated cytochrome c release, and significantly suppresses tumor growth in a subcutaneous HCC mouse model[58].

Berberine: An isoquinoline alkaloid whose anti-HCC effect is closely related to reshaping the tumor immune microenvironment. In an orthotopic HCC mouse model, berberine reduced tumor burden by enhancing the effector function of CD8⁺ T lymphocytes and regulating intrahepatic T cell heterogeneity, as revealed by CyTOF and single-cell RNA-sequencing analyses[59]. Furthermore, the combination of berberine with anti-PD-L1 (0-50 μM in vitro; in vivo validation in mouse models) markedly inhibited HCC tumorigenesis and metastasis by inactivating ERK signaling pathway phosphorylation[60].

Solamargine: A steroidal alkaloid that inhibits HCC cell proliferation and effectively induces apoptosis and autophagy via the LIF/miR-192-5p/CYR61/AKT signaling axis. In PDX and orthotopic HCC mouse models, solamargine significantly slowed tumor growth and drove the repolarization of tumor-associated macrophages from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype via LIF/p-STAT3-mediated pathways[61].

Protopine: An isoquinoline alkaloid derived from Jinlingzi Powder, identified as a key component responsible for the propyroptotic activity of Jinlingzi Powder[62]. It induces pyroptosis in HCC cells by activating the caspase1/GSDMD pathway, promoting interleukin (IL)-1β and IL-18 release, an effect that can be reversed by the inhibitor VX765[62].

Alkaloids exert anti-HCC effects by directly targeting key proteins involved in metastasis and by reshaping the tumor immune microenvironment. Matrine directly binds to MMP-9, while solamargine and berberine exemplify the immunomodulatory potential of this class. Notably, solamargine’s use of PDX models provides stronger translational relevance than conventional xenografts.

Terpenoids and volatile oils

Terpenoids are composed of isoprene units with rich structural variations, possessing diverse anti-cancer mechanisms. Recent reviews on phytochemicals have systematically highlighted the anti-HCC activities of terpenoids, together with other natural products[54].

Ailanthone: A triterpenoid compound that inhibits HCC cell proliferation by suppressing PINK1-Parkin-mediated mitophagy, promoting BAX-BAK1 pore formation, leading to mtDNA leakage into the cytoplasm, which triggers the release of inflammatory factors such as tumor necrosis factor alpha, IL-1β, and IL-6[63]. In vivo, ailanthone (5-15 mg/kg i.p.) significantly reduces tumor growth in Huh7 xenograft models without obvious adverse effects[63].

Cucurbitacin B: Belongs to the tetracyclic triterpenoids. Network pharmacology, molecular docking, and experimental validation indicate that its anti-HCC action involves inhibiting the PI3K-AKT signaling pathway via stable binding to core targets including EGFR, mTOR, and HSP90AB1[64]. In vitro, cucurbitacin B suppresses Huh7, Hep3B, and Hepa1/6 cell growth and induces G2/M arrest via ATM-dependent p53-p21-CDK1 and CHK1-CDC25C signaling without directly triggering apoptosis; in vivo, it significantly inhibits tumor growth in BALB/c mice bearing Hepa1/6 cells and in HepG2 xenograft models[65]. Clinically, cucurbitacin-containing tablets have been used as adjuvant therapy for chronic hepatitis and primary liver cancer since the 1970s-1980s, though modern randomized controlled trials are lacking[65].

Celastrol: A quinone methide triterpenoid exerting multi-pathway anti-HCC effects. Recent research reveals celastrol suppresses HCC via a novel non-coding RNA regulatory axis: Celastrol down-regulates circ_SLIT3, which acts as a miR-223-3p sponge to control CXCR4 expression, thereby repressing HCC cell proliferation, migration, and invasion[66]. Moreover, celastrol directly binds to VDAC2, inducing ROS-mediated ferroptosis and apoptosis[67], and modulates gut microbiota to elevate GUDCA, which blocks FXR/RXRα heterodimerization and inhibits mTOR/S6K1 signaling[68].

Oridonin: A diterpenoid compound. A recent review confirms that oridonin inhibits HCC through multiple mechanisms involving ROS, EGFR, NF-κB, PI3K/AKT, and MAPK signaling pathways[69]. In HepG2 cells, oridonin induces G2/M arrest and mitochondrial apoptosis via ROS generation and caspase activation[70].

Carvacrol: A monoterpenoid phenol. Network pharmacology and molecular docking studies identified anti-HCC targets including AURKA and AGRN[71]. Experimental validation confirms that carvacrol (IC₅₀ = 24.2 μM in HepG2 cells) inhibits proliferation and induces mitochondrial-mediated apoptosis via the MAPK pathway[72]. In vivo, carvacrol (15 mg/kg/day, oral) combined with sorafenib significantly improves survival rate and attenuates HCC progression in rat models, while mitigating sorafenib-induced cardiotoxicity via TRPM7 inhibition[73].

Celastrus orbiculatus extract: An extract rich in terpenoid compounds. Celastrus orbiculatus extract (COE) inhibits vasculogenic mimicry (VM) formation in HCC through dual mechanisms: (1) Downregulating Notch1 signaling; and (2) Targeting EphA2. In vitro, COE (0-160 μg/mL) inhibits HCC cell proliferation and invasion in a concentration-dependent manner, and blocks TGF-β1-induced VM formation[74]. In vivo, COE (oral gavage) significantly inhibits tumor growth and VM formation by downregulating Notch1 and Hes1 expression[74]. Subsequent proteomics analysis further identified EphA2 as a direct target, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD regulation[75].

Terpenoids exert anti-HCC effects through diverse mechanisms. Ailanthone uniquely blocks mitophagy leading to mtDNA leakage and inflammatory response. Cucurbitacin B inhibits the PI3K/AKT/mTOR pathway, while celastrol modulates the gut microbiota-bile acid-FXR axis to suppress mTOR/S6K1 signaling. COE is one of the few extracts with a clearly defined molecular target (EphA2), strengthening its translational rationale.

Quinones

Quinones possess an unsaturated cyclic diketone structure and often exert biological activity through redox cycling and interfering with electron transfer processes.

Emodin: The main anthraquinone component in Polygonum multiflorum. In vitro (Bel-7402, IC₅₀ 100 μmol/L), emodin induces intrinsic mitochondrial apoptosis (reduced ΔΨm, cytochrome c release) and inhibits SREBP1-mediated fatty acid synthesis through both SREBP1-dependent and -independent pathways[76]. A 2026 study demonstrated that emodin (25 mg/kg or 50 mg/kg i.p.) triggers cuproptosis to suppress HCC via the SLC7A11/FDX1 axis in HCCLM3 xenograft models[77]. However, high-dose or long-term emodin use may cause hepatotoxicity; its poor oral bioavailability and narrow therapeutic window remain major translational hurdles[78].

Hypericin: A naphthodianthrone compound. In Huh7 cells, hypericin exhibits dose-dependent cytotoxicity (24-hour LD₅₀ = 2 μg/mL) and selectively induces apoptosis (53% apoptotic rate at 24 hours) via upregulation of p53 and Bax expression, with no significant effect on normal fibroblasts[79]. In vivo, hypericin significantly suppresses tumor growth and reduces M2 macrophage polarization in tumor tissues via inhibition of the PI3K/AKT signaling pathway[80]. However, poor water solubility and low oral bioavailability limit its clinical translation[81].

Shikonin: A naphthoquinone compound. In HCC cells, shikonin (0-0.4 μM) suppresses HCC cell migration by inhibiting AKT/NF-κB activation, downregulating MMP-2, MMP-9, and vimentin expression[82]. As a specific PKM2 inhibitor, shikonin can effectively attenuate PKM2-dependent glycolysis, growth, and metastasis in HCC in vitro and in orthotopic mouse models[83]. Pharmacokinetic challenges, such as poor water solubility, have been noted[84].

Quinones exert anti-HCC effects primarily by inducing mitochondrial apoptosis, inhibiting metastasis, and interfering with metabolic pathways. Recent discoveries of emodin-induced cuproptosis and shikonin’s targeting of PKM2 highlight novel mechanisms, though pharmacokinetic optimization remains essential.

Other structural categories

Besides the main categories above, recent reviews on phytochemicals have also highlighted the anti-HCC potential of monomers from other structural classes[54].

Phenolic acids and derivatives: (1) Curcumin: A polyphenolic compound with poor water solubility and low oral bioavailability. To overcome these drawbacks, nano-encapsulation strategies (e.g., silica-chitosan) have been employed, which enhance its stability and cytotoxicity against HepG2 cells in vitro and significantly suppress tumor growth in xenograft models[85]. A 2025 systematic review further confirms that curcumin modulates multiple signaling pathways in HCC, including PI3K/AKT/mTOR, JAK2/STAT3, MAPK, and Wnt/β-catenin; however, clinical translation remains limited by the lack of human studies[86]; (2)·Zingerone: A phenolic compound. Zingerone monotherapy (0.5-4 μM in vitro; 30 mg/kg oral in xenograft mice) suppresses HCC proliferation, invasion, and tumor growth by inhibiting the MTDH-mediated PI3K/AKT pathway[87]. When combined with its novel derivative, zingerone synergistically inhibits TGF-β1-induced EMT, migration, and invasion in HCC cells[88]; (3)·Echinacea purpurea extract: Rich in caffeic acid derivatives and other phenolic acids. An ethanol extract significantly suppresses HCC cell proliferation, migration, and invasion both in vitro (Hepa1-6, HepG2) and in vivo (C57BL/6J mouse model, 150 mg/kg body weight), with the PI3K/AKT pathway identified as the key downstream mediator[89]. Subsequent studies have further elucidated that a purified polysaccharide (200 mg/kg/day, p.o.) effectively alleviates HCC-induced liver injury by modulating gut microbiota to suppress the TLR4/NF-κB pathway, and facilitates M1 macrophage polarization[90]; and (4) Gallic acid: A trihydroxybenzoic acid. Mechanistically, gallic acid (GA) induces ferroptosis in HCC cells by inhibiting the expression of SLC7A11 and GPX4, thereby blocking β-catenin nuclear transport and inactivating the Wnt/β-catenin pathway[91]. In the context of liver cancer, GA also modulates the NF-κB, Wnt/β-catenin, and JAK/STAT3 signaling pathways[92]. In vivo, GA demonstrates chemopreventive and antiproliferative effects, as it has been shown to inhibit the progression of diethylnitrosamine-induced hepatocarcinogenesis in rat models[93].

Lignans (purified vitexin compound 1): A neolignan derived from Vitex negundo seeds. Vitexin compound 1 exerts anti-HCC effects via the “AKT/ERK-FOXO3a-apoptosis” axis by inhibiting AKT and ERK1/2 phosphorylation, relieving the inhibition on FOXO3a, promoting its nuclear translocation and transcriptional activity, thereby inducing apoptosis in HepG2, Hep3B, and Huh-7 cells[94]. The study is limited to in vitro experiments; no IC₅₀ values or in vivo tumor growth data are reported.

Polysaccharides (bletilla striata polysaccharide): A natural macromolecular polysaccharide used as a vascular embolizing agent in interventional therapy for primary liver cancer. Beyond its embolic function, recent studies demonstrate that bletilla striata polysaccharide (BSP) induces G1 phase arrest and triggers apoptosis through the mitochondrial pathway, with low-molecular-weight BSP showing an IC₅₀ of 27.2 μg/mL at 24 hours and 14.8 μg/mL at 48 hours against HepG2 cells[95]. In vivo, BSP (50 mg/kg, 100 mg/kg, 200 mg/kg, i.p.) significantly inhibits tumor growth in H22 tumor-bearing mice and improves immune cell activities in a dose-dependent manner[95].

Triterpenic acids (18β-glycyrrhetinic acid): The main active component of licorice. 18β-glycyrrhetinic acid (18β-GA) (at 50 μmol/L, 100 μmol/L, 200 μmol/L) inhibits migration and invasion of SMMC-7721 cells, downregulates β-catenin and TCF4 expression, and suppresses TGF-β-induced EMT and metastasis in HCC cells via the SHP1/SHP2/STAT3/Snail pathway[96]. In vivo, a novel 18β-GA-tetramethylpyrazine conjugate TOGA (10 mg/kg, i.p.) significantly prevents tumor growth in both subcutaneous and orthotopic liver cancer models with little toxicity[97]. However, recent pharmacokinetic studies confirm that 18β-GA is poorly absorbed after oral administration, highlighting the need for novel delivery strategies[98].

Sterols (taraxasterol): A sterol from Taraxacum officinale. In vitro, taraxasterol significantly inhibits the proliferation, induces apoptosis, and blocks the cell cycle in HepG2 and Huh7 cells[99]. In vivo, taraxasterol (5 mg/kg and 7.5 mg/kg, i.p.) suppresses tumor growth in H22 mice and enhances T-cell immunity via the IL-6/STAT3 pathway[99]. Pharmacokinetic data (bioavailability, half-life) and long-term toxicity studies are lacking.

Multi-component extracts: (1) Glehnia littoralis extract (GLE): Induces apoptosis in Hep3B cells (IC₅₀ = 300 μg/mL) via the p38/JNK MAPK pathway, with RNA-seq confirming increased expression of pro-apoptotic genes including GADD45B/G[100]. Data are limited to a single cell line; in vivo validation is lacking; (2) Marsdeniae tenacissima extract: A standardized extract approved for clinical use (brand name: Xiaoai Ping). Marsdeniae tenacissima extract inhibits proliferation and induces autophagy, apoptosis, and Sphase arrest in MHCC97H and HepG2 cells[101]. Additionally, it suppresses tumor growth and angiogenesis in HCC-PDX models via downregulating VEGFA, PDGFRB, and VWF[102]. However, detailed doseresponse data and comprehensive pharmacokinetic profiles remain limited; (3)·Zanthoxylum avicennae extracts: In HA22T cells, the extract activates PP2A, leading to GSK-3β upregulation and β-catenin degradation, thereby inhibiting Wnt/β-catenin signaling and blocking metastasis. In vivo, YBBE treatment suppresses tumor growth in xenograft nude mice[103]; (4)·Ethyl acetate fraction of dill seeds: Induces G2/M arrest and mitochondria-mediated apoptosis (MMP loss, ROS accumulation, caspases-3/caspases-7/caspases-9 activation) in HepG2 cells (0.1-0.8 mg/mL)[104]. The study lacks in vivo validation and a detailed analysis of its bioactive principles; and (5)·Acokanthera oppositifolia extract (rich in cardiac glycosides such as ouabain and acovenoside A): A 2025 review further highlights the anticancer potential of ouabain – a representative cardiac glycoside – in tumor development and progression, emphasizing its clinical promise[105].

These multi-component extracts highlight the diversity of anti-HCC natural products, but their clinical development is often hindered by undefined active principles and, in some cases, limited pharmacokinetic characterization.

To provide a concise overview of representative monomers across all structural classes, we summarize their primary mechanisms, key molecular events, and signaling pathways in Table 1[12-17,19-23,27,28,30,31,33-42,44-47,49-51,55-72,74-77,79-80,82,83,86-92,94-96,99-105].

Table 1 Summary of representative anti-hepatocellular carcinoma Chinese herbal monomers by structural class, mechanism category and key pathways.

Item	Monomer	Mechanism	key pathway/molecular events	Ref.
Saponins	PD	Inducing programmed cell death	Mitochondria-mediated apoptosis: Bax/Bcl-2 ratio (increase) → activation of caspase-9/3	Li et al[12]
		Inducing programmed cell death	Protective autophagy (ERK-dependent + JNK-dependent)	Li et al[12]
		Inducing programmed cell death	Downregulation of BIRC5 (survivin) expression	Kapewangolo et al[14], Song et al[15]
		Modulating TME and immune response	Immunomodulatory potential (specific pathways remain to be further elucidated)	Kapewangolo et al[14], Song et al[15]
		Reversing multidrug resistance and chemosensitization	Inhibition of ERK1/2 → cofilin-1 phosphorylation (decreased) → reversing HDAC resistance	Hsu et al[13]
	Notoginsenoside Ft1	Inducing programmed cell death	Inhibition of PI3K/AKT/mTOR signaling pathway → induction of both apoptosis and lysosome-dependent cell death (a unique form of PCD)	Jeon et al[16]
	Tubeimoside I	Inducing programmed cell death	Upregulation of TNFAIP3 → negative feedback inhibition of NF-κB signaling pathway → induction of apoptosis (confirmed by in vitro and in vivo dose-dependent cell growth inhibition)	Zhang et al[17]
	Astragaloside IV	Inducing programmed cell death	Induction of apoptosis in SK-Hep1 and Hep3B cells	Su et al[19]
		Inducing programmed cell death	Induction of G1 phase cell cycle arrest in SK-Hep1 and Hep3B cells	Su et al[19]
		Suppressing invasion, metastasis and EMT	Inhibition of HCC progression via TGF-β/Smad pathway (in DEN-induced fibrosis-HCC mouse model)	Zhang et al[20]
		Modulating TME and immune response	Inhibition of HCC progression via Nrf2/HO-1 pathway (in DEN-induced fibrosis-HCC mouse model)	Zhang et al[20]
		Reversing multidrug resistance and chemosensitization	Reversing cisplatin resistance by suppressing MRP2 (in H22 tumor-bearing mice, 40 mg/kg i.g.)	Qu et al[21]
	TAIII	Inducing programmed cell death	Mitochondria-dependent apoptosis: Activation of caspases + release of cytochrome C, HtrA2/Omi, and Smac/Diablo from mitochondria	Wang et al[22]
		Inducing programmed cell death	Degradation of XIAP via AMPKα/mTOR-dependent autophagic-lysosomal pathway	Wang et al[22]
		Inducing programmed cell death	Concentration-dependent and time-dependent proliferation suppression and apoptosis promotion in HepG2 cells	Nho et al[23]
	α-Hederin	Suppressing invasion, metastasis and EMT	Inhibits HCC metastasis by targeting the PAF/PTAFR signaling axis, subsequently suppressing downstream STAT3 and MMP-2 expression (demonstrated in in vitro and lung metastasis models)	Cao et al[27]
	Paeoniflorin	Modulating TME and immune response	Targets SRC kinase, blocking norepinephrine-induced activation of hepatic stellate cells and inhibiting malignant crosstalk between neuroendocrine signaling and the tumor microenvironment (demonstrated in chronic restraint stress-HCC mouse model, 50 mg/kg i.g.)	Luo et al[28]
Flavonoids	Scutellarein	Inducing programmed cell death	Extrinsic apoptosis: Activation of death receptor pathway (Fas/FasL → caspase-8/3)	Sang Eun et al[30]
		Inducing programmed cell death	G2/M phase cell cycle arrest via downregulation of Cdc25C, CDK1, and cyclin B1 → inhibition of proliferation	Sang Eun et al[30]
	Kaempferol	Inducing programmed cell death	Induces G2/M phase arrest through regulation of the ATM/CHEK2/KNL1 pathway in HCCLM3 and Huh7 cells (reduced tumor growth confirmed in three-dimensional tumor spheroid models)	Li et al[31]
	Hydroxygenkwanin	Suppressing invasion, metastasis and EMT	Inducing miR-320a expression → inhibiting FOXM1 and FOXM1-mediated EMT → curbing tumor proliferation and invasion	Chou et al[33]
		Reversing multidrug resistance and chemosensitization	Enhancing chemosensitivity by inhibiting DNA damage response	Chen et al[34]
	Licochalcone A	Inducing programmed cell death	Inducing ferroptosis via the SLC7A11/GPX4 pathway → ROS accumulation and lipid peroxidation; also regulates non-coding RNA	Zhang et al[35], Liu et al[36]
	Baicalein/Baicalin/Wogonin	Inducing programmed cell death	Inducing G0/G1 phase arrest via a β-catenin-dependent mechanism in Bel-7404 and HepG2 cells	Zheng et al[37]
		Suppressing invasion, metastasis and EMT	Suppressing the MEKERK signaling pathway → downregulating MMP-2, MMP-9 and u-PA expression → inhibiting HCC metastasis	Chen et al[38]
		Modulating TME and immune response	Inducing repolarization of tumor-associated macrophages from M2-like to M1-like phenotype via autophagy-associated activation of RelB/p52 → completely blocks orthotopic growth of implanted HCC	Tan et al[39]
		Inducing programmed cell death	Suppressing proliferation and inducing apoptosis of HepG2 and Bel7402 cells through multiple pathways	Liu et al[40]
		Modulating TME and immune response	Directly suppressing STAT3 phosphorylation → downregulating immunosuppressive molecules → promoting recruitment of dendritic cells, T cells and NK cells into tumor tissues	Xiao et al[41]
	Chrysin	Inducing programmed cell death	Targeting HK2 → blocking tumor glycolysis while simultaneously inducing mitochondriadependent apoptosis (metabolism-apoptosis dual mechanism)	Xu et al[42]
	Eupafolin	Inhibiting angiogenesis and VM	Directly inhibiting VEGF/VEGFR2 signaling in HUVECs while also reducing VEGF secretion from HepG2 cells → reducing microvessel density in xenograft models (dual pathway: “Targeting endothelium-inhibiting secretion”)	Jiang et al[44]
	Hydroxysafflor yellow A	Inhibiting angiogenesis and VM	Suppressing p38 MAPK phosphorylation → inhibiting downstream p38 MAPK/ATF-2 signaling pathway; additionally modulates tumor vascularization through intercellular communication and extracellular matrix-receptor interactions	Zhang et al[45], Xue et al[46]
	Puerarin	Inducing programmed cell death	Inhibits SMMC-7721 cell proliferation and induces apoptosis via the mitochondria-dependent pathway	Zhang et al[47]
		Inhibiting angiogenesis and VM	Nanoformulation (nanoPue) significantly suppresses tumor growth and enhances chemosensitivity via regulating NSUN2 and inhibiting angiogenesis	Feng et al[49]
		Inducing programmed cell death	Suppresses HCC progression by blocking the PI3K/AKT/mTOR pathway	Murahari et al[50]
	Icaritin	Modulating TME and immune response	Modulating the tumor immune microenvironment by enhancing the anti-tumor function of CD8+ T cells, inhibiting MDSCs, and regulating multiple cytokines	Qin et al[51]
Alkaloids	Matrine	Inducing programmed cell death	Prevents the early development of HCC-like lesions by suppressing Notch1 and Hes1 activation	Shi et al[55]
		Suppressing invasion, metastasis and EMT	Inhibits cancer metastasis by directly targeting MMP-9	Zhang et al[56]
		Modulating TME and immune response	Regulates tumor-associated coagulation abnormalities by targeting PLG	Zhou et al[57]
	Aconitine	Inducing programmed cell death	Induces apoptosis through upregulation of Bax, downregulation of Bcl-2, activation of caspases 3 and 7, and promotion of ROS-mediated cytochrome C release	Qi et al[58]
	Berberine	Modulating TME and immune response	Reduced tumor burden by enhancing the effector function of CD8+ T lymphocytes and regulating intrahepatic T cell heterogeneity	Hu et al[59]
		Inducing programmed cell death	In combination with anti-PD-L1, markedly inhibited HCC tumorigenesis and metastasis by inactivating ERK signaling pathway phosphorylation	Miao et al[60]
	Solamargine	Inducing programmed cell death	Inhibits HCC cell proliferation and effectively induces apoptosis and autophagy via the LIF/miR-192-5p/CYR61/AKT signaling axis	Yin et al[61]
		Modulating TME and immune response	Drove the repolarization of TAMs from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype via LIF/p-STAT3-mediated pathways	Yin et al[61]
	Protopine	Inducing programmed cell death	Induces pyroptosis in HCC cells by activating the caspase-1/GSDMD pathway, promoting IL-1β and IL-18 release	Liu et al[62]
Terpenoids and volatile oils	Ailanthone	Inducing programmed cell death	Inhibits HCC cell proliferation by suppressing PINK1-Parkin-mediated mitophagy, promoting BAX-BAK1 pore formation, leading to mtDNA leakage into the cytoplasm, which triggers the release of inflammatory factors such as TNF-α, IL-1β, and IL-6	Qin et al[63]
	Cucurbitacin B	Inducing programmed cell death	Inhibiting the PI3K-AKT signaling pathway via stable binding to core targets including EGFR, mTOR, and HSP90AB1	Zhang et al[64]
		Inducing programmed cell death	Induces G2/M arrest via ATM-dependent p53-p21-CDK1 and CHK1-CDC25C signaling without directly triggering apoptosis	Li et al[65]
	Celastrol	Suppressing invasion, metastasis and EMT	Down-regulates circ_SLIT3, which acts as a miR-223-3p sponge to control CXCR4 expression, thereby repressing HCC cell proliferation, migration, and invasion	Si et al[66]
		Inducing programmed cell death	Directly binds to VDAC2, inducing ROS-mediated ferroptosis and apoptosis	Luo et al[67]
		Modulating TME and immune response	Modulates gut microbiota to elevate GUDCA, which blocks FXR/RXRα heterodimerization and inhibits mTOR/S6K1 signaling	Zeng et al[68]
	Oridonin	Inducing programmed cell death	Inhibits HCC through multiple mechanisms involving ROS, EGFR, NF-κB, PI3K/AKT, and MAPK signaling pathways	Gao et al[69]
		Inducing programmed cell death	Induces G2/M arrest and mitochondrial apoptosis via ROS generation and caspase activation	Wang et al[70]
	Carvacrol	Inducing programmed cell death	Identified anti-HCC targets including AURKA and AGRN	Liu et al[71]
		Inducing programmed cell death	Inhibits proliferation and induces mitochondrial-mediated apoptosis via the MAPK pathway	Yin et al[72]
	COE	Inhibiting angiogenesis and VM	Inhibits VM formation through dual mechanisms: Downregulating Notch1 signaling and targeting EphA2 (involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD regulation)	Jue et al[74], Chen et al[75]
Quinones	Emodin	Inducing programmed cell death	Induces intrinsic mitochondrial apoptosis (reduced ΔΨm, cytochrome C release) and inhibits SREBP1-mediated fatty acid synthesis through both SREBP1-dependent and independent pathways	Yang et al[76]
		Inducing programmed cell death	Triggers cuproptosis to suppress HCC via the SLC7A11/FDX1 axis	Chen et al[77]
	Hypericin	Inducing programmed cell death	Selectively induces apoptosis via upregulation of p53 and Bax expression	Olya et al[79]
		Modulating TME and immune response	Reduces M2 macrophage polarization in tumor tissues via inhibition of the PI3K/AKT signaling pathway	Wen et al[80]
	Shikonin	Suppressing invasion, metastasis and EMT	Suppresses HCC cell migration by inhibiting AKT/NF-κB activation, downregulating MMP-2, MMP-9, and vimentin expression	Wei et al[82]
		Suppressing invasion, metastasis and EMT	As a specific PKM2 inhibitor, attenuates PKM2-dependent glycolysis, growth, and metastasis in HCC	Liu et al[83]
Phenolic Acids and Derivatives	Curcumin	Inducing programmed cell death	Modulates multiple signaling pathways in HCC, including PI3K/AKT/mTOR, JAK2/STAT3, MAPK, and Wnt/β-catenin	Esmaeli et al[86]
	Zingerone	Suppressing invasion, metastasis and EMT	Suppresses HCC proliferation, invasion, and tumor growth by inhibiting the MTDH-mediated PI3K/AKT pathway	Fang et al[87]
		Suppressing invasion, metastasis and EMT	In combination with its novel derivative, synergistically inhibits TGF-β1-induced EMT, migration, and invasion in HCC cells	Kim et al[88]
	Echinacea purpurea Extract	Suppressing invasion, metastasis and EMT	Significantly suppresses HCC cell proliferation, migration, and invasion, with the PI3K/AKT pathway identified as the key downstream mediator	Xu et al[89]
		Modulating TME and immune response	Alleviates HCC-induced liver injury by modulating gut microbiota to suppress the TLR4/NF-κB pathway, and facilitates M1 macrophage polarization	Jing et al[90]
	GA	Inducing programmed cell death	Induces ferroptosis in HCC cells by inhibiting the expression of SLC7A11 and GPX4, thereby blocking β-catenin nuclear transport and inactivating the Wnt/β-catenin pathway	Xie et al[91]
		Inducing programmed cell death	Modulates the NF-κB, Wnt/β-catenin, and JAK/STAT3 signaling pathways	Li et al[92]
Lignans	Purified vitexin compound 1	Inducing programmed cell death	Exerts anti-HCC effects via the “AKT/ERK-FOXO3a-apoptosis” axis by inhibiting AKT and ERK1/2 phosphorylation, relieving the inhibition on FOXO3a, promoting its nuclear translocation and transcriptional activity, thereby inducing apoptosis	Wang et al[94]
Polysaccharides	BSP	Inducing programmed cell death	Induces G1 phase arrest and triggers apoptosis through the mitochondrial pathway	Liu et al[95]
		Modulating TME and immune response	Improves immune cell activities in a dose-dependent manner	Liu et al[95]
Triterpenic Acids	18β-GA	Suppressing invasion, metastasis and EMT	Inhibits migration and invasion of SMMC-7721 cells, downregulates β-catenin and TCF4 expression, and suppresses TGF-β-induced EMT and metastasis in HCC cells via the SHP1/SHP2/STAT3/Snail pathway	Jie et al[96]
Sterols	TS	Inducing programmed cell death	Significantly inhibits proliferation, induces apoptosis, and blocks the cell cycle in HepG2 and Huh7 cells	Ren et al[99]
		Modulating TME and immune response	Enhances T-cell immunity via the IL-6/STAT3 pathway	Pan et al[102]
Multi-component extracts	GLE	Inducing programmed cell death	Induces apoptosis in Hep3B cells via the p38/JNK MAPK pathway, with RNA-seq confirming increased expression of pro-apoptotic genes including GADD45B/G	Park et al[100]
	MTE	Inducing programmed cell death	Inhibits proliferation and induces autophagy, apoptosis, and S-phase arrest in MHCC-97H and HepG2 cells	Lin et al[101]
		Inhibiting angiogenesis and VM	Suppresses tumor growth and angiogenesis in HCC-PDX models via downregulating VEGFA, PDGFRB, and VWF	Pan et al[102]
	Zanthoxylum avicennae extracts	Suppressing invasion, metastasis and EMT	Activates PP2A, leading to GSK-3β upregulation and β-catenin degradation, thereby inhibiting Wnt/β-catenin signaling and blocking metastasis	Wu et al[103]
	EAFD	Inducing programmed cell death	Induces G2/M arrest and mitochondria-mediated apoptosis (MMP loss, ROS accumulation, caspases-3/caspases-7/caspases-9 activation) in HepG2 cells	Mohammed et al[104]
	Acokanthera oppositifolia extract	Inducing programmed cell death	Induces energy crisis-mediated necrosis in HepG2 cells by depleting ATP, disrupting mitochondrial membrane potential, and reducing GSH levels, thereby overcoming apoptotic resistance in HCC	Nik Nabil et al[105]

HCC: Hepatocellular carcinoma; EMT: Epithelial-mesenchymal transition; PD-L1: Programmed cell death-ligand 1; TNF-α: Tumor necrosis factor alpha; TNFAIP3: Tumor necrosis factor alpha-induced protein 3; MDSCs: Myeloid-derived suppressor cells; PLG: Plasminogen; IL: Interleukin; COE: Celastrus orbiculatus extract; VM: Vasculogenic mimicry; GA: Gallic acid; BSP: Bletilla striata polysaccharide; TS: Taraxasterol; GLE: Glehnia littoralis extract; EAFD: Ethyl acetate fraction of dill seeds; MMP: Matrix metalloproteinase; MEK: Mitogen-activated protein kinase; JNK: C-Jun N-terminal kinase; TME: Tumour microenvironment; PCD: Programmed cell death; TGF-β: Transforming growth factor beta; ROS: Reactive oxygen species; u-PA: Urokinase-type plasminogen activator; TAMs: Tumor-associated macrophages; ATP: Adenosine triphosphate; GSH: Glutathione; ERK: Extracellular signal-regulated kinases; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; IL: Interleukin; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor-kappa B; MAPK: Mitogen-activated protein kinases; PD: Platycodin D; PDX: Patient-derived xenografts; 18β-GA: 18β-glycyrrhetinic acid; NK: Natural killer.

SUMMARY OF MAIN FINDINGS

This review systematically summarizes Chinese herbal monomers with anti-HCC activity and, for the first time from the perspective of chemical structure classification, elaborates on the mechanisms of action of representative monomers from saponins, flavonoids, alkaloids, terpenoids, quinones, and other categories. Research indicates that Chinese herbal monomers exert anti-HCC effects through a complex, synergistic multi-dimensional network (Figure 1). Their main characteristics can be summarized as follows.

Figure 1 Schematic overview of key mechanisms in hepatocarcinogenesis and their modulation by Chinese herbal monomers. It illustrates the core biological processes including tumor cell proliferation, apoptosis, autophagy, ferroptosis, cell cycle progression, epithelial-mesenchymal transition, angiogenesis, metastasis, drug resistance and immune evasion, as well as the intervention targets of Chinese herbal monomers in these processes. EMP: Endothelial microparticles; STAT3: Signal transducer and activator of transcription 3; MMP: Matrix metalloproteinase; JAK: Janus kinase; IL-6: Interleukin-6; HCC: Hepatocellular carcinoma; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; MDSC: Myeloid-derived suppressor cell; VM: Vasculogenic mimicry.

Broad mechanisms of action

Chinese herbal monomers intervene in almost all key processes of HCC development and progression, including directly inducing various forms of programmed cell death (apoptosis, autophagy, ferroptosis, pyroptosis, cuproptosis); inhibiting proliferation by arresting the cell cycle (G1/S, G2/M); curbing metastasis by inhibiting EMT and invasion-related proteins (e.g., MMPs); indirectly suppressing tumors by modulating immune responses, metabolic reprogramming, and angiogenesis within the tumor microenvironment; and in some cases, enhancing the sensitivity of existing drugs or reversing chemotherapy resistance.

Cross-intervention in signaling pathways

The “multi-target” characteristic of Chinese herbal monomers is reflected in their synergistic regulation of multiple core signaling pathways in HCC, such as PI3K/AKT/mTOR, NF-κB, MAPK (ERK, JNK), Wnt/β-catenin, and JAK/STAT, forming a complex network intervention (Figure 2). This may be the structural basis for their potential to overcome single-target drug resistance.

Figure 2 Heatmap of associations between structurally classified Chinese herbal monomers and key signaling pathways in hepatocellular carcinoma. The heatmap shows the regulatory intensity of different types of Chinese herbal monomers (saponins, flavonoids, alkaloids, terpenoids, quinones, etc.) on classical signaling pathways (phosphatidylinositol 3-kinase/protein kinase B /mechanistic target of rapamycin, nuclear factor-kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, Wnt/β-catenin, etc.) in Hepatocellular carcinoma.

Emerging structure-activity relationships

Despite structural diversity, monomers within the same class show certain tendencies in their mechanisms of action. For example, saponins are prominent in inducing multiple forms of cell death (apoptosis, autophagy) and inhibiting metastasis; flavonoids excel at inducing cell cycle arrest and oxidative stress (e.g., ferroptosis); alkaloids are notable for inducing diverse programmed cell death modes and reshaping the tumor immune microenvironment; and terpenoids demonstrate unique capabilities in modulating mitophagy and VM. This preliminary structureclass-mechanism association provides valuable clues for further structurebased drug design and optimization.

COMPARISON WITH EXISTING LITERATURE

Compared to previous reviews that primarily categorize anti-HCC mechanisms by biological processes or list monomers without systematic organization, this review introduces a novel perspective by systematically classifying monomers according to their chemical structures. This structure-based approach not only clarifies the correlations between compound classes and their preferred pharmacological mechanisms but also provides a practical framework for structure-guided drug development and lead optimization. Furthermore, this review critically assesses the quality and reliability of available evidence, distinguishing between preliminary in vitro findings and results validated in clinically relevant models such as orthotopic or PDX. A systematic verification of cited literature was also performed to ensure citation accuracy, an issue that has not been systematically addressed in prior publications but is essential for maintaining the rigor of evidence synthesis.

CHALLENGES FOR CLINICAL TRANSLATION

Despite the great potential shown by Chinese herbal monomers in anti-HCC research, their translation from basic research to clinical application still faces numerous challenges (Table 2)[22,24,25,43,48,49,51-53,55,56,59,60,64,65,85,86,96-98,101,102].

Table 2 Clinical translation status of representative anti-hepatocellular carcinoma Chinese herbal monomers.

Compound/extract	Structural class	Highest clinical stage (HCC)	Key findings	Key issues	Ref.
Icaritin	Prenylflavonoid	Phase II/III (China), combined with TACE + lenvatinib	Improved ORR, DCR, PFS in unresectable HCC with poor prognosis; real-world DCR 60.0% (mono)/93.8% (combo); grade 3 TRAEs 13.9%, no grade ≥ 4; immunomodulatory activity confirmed	Phase III data still awaited.	Qin et al[51], Lu et al[52], He et al[53]
Cucurbitacin B	Tetracyclic triterpenoid	Preclinical	Induces G2/M arrest via ATM-dependent p53-p21-CDK1 and CHK1-CDC25C pathways	Lack of modern clinical trials; poor PK limits development	Zhang et al[64], Li et al[65]
MTE (Xiaoai Ping)	Steroidal saponin – rich extract	Approved and marketed in China	Long-term clinical use as an adjuvant antitumour agent	Few highquality RCTs against current standard-of-care; PK/PD data limited	Lin et al[101], Pan et al[102]
Curcumin	Polyphenol	Phase I/II (various solid tumours, limited HCC-specific)	Oral bioavailability < 1% due to poor solubility and rapid metabolism	Nanoformulations remain preclinical; no convincing monotherapy efficacy in HCC patients	Shelash Al-Hawary et al[85], Esmaeli et al[86]
Berberine	Isoquinoline alkaloid	Preclinical/early-stage combination trials	Potent immunomodulation (CD8+ T cell reprogramming) and synergy with anti-PD-L1 in animal models	No published phase II/III data for HCC monotherapy	Hu et al[59], Miao et al[60]
Matrine	Quinolizidine alkaloid	Preclinical	Inhibits metastasis via MMP-9 targeting and Notch1/Hes1 suppression; prevents early HCC-like lesions in rat model	No clinical trial data for HCC monotherapy	Shi et al[55], Zhang et al[56]
Puerarin	Isoflavone	Preclinical only; nanoformulations in animal studies	Nanoformulation (nanoPue) shows enhanced anti-HCC activity via NSUN2 regulation and angiogenesis inhibition in preclinical models	Extremely poor water solubility and oral bioavailability; no clinical efficacy data in HCC patients	He et al[48], Feng et al[49]
Chrysin	Flavonoid	Preclinical only	-	Oral bioavailability 0.003%-0.02%, Cmax 12-64 nM; no human PK or efficacy data	Dabiri et al[43]
TAIII	Steroidal saponin	Preclinical only	Potent anti-HCC activity in vitro and in vivo	Extremely low oral bioavailability (9.18%) and hepatotoxicity concerns; liposomal formulations still preclinical	Wang et al[22], Zhang et al[24], Lin et al[25]
18β-GA	Triterpenic acid	Preclinical only	Conjugates (e.g., TOGA) show improved efficacy in animal models	Poor oral absorption and rapid systemic clearance	Jie et al[96], Wang et al[97], Li et al[98]

HCC: Hepatocellular carcinoma; PD-L1: Programmed cell death-ligand 1; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression-free survival; MTE: Marsdeniae tenacissima extract; MMP: Matrix metalloproteinase; TACE: Transarterial chemoembolization; TRAEs: Treatment-related adverse events; PK: Pharmacokinetics; RCTs: Randomized controlled trials; PD: Pharmacodynamic; 18β-GA: 18β-glycyrrhetinic acid.

Suboptimal pharmacokinetic properties

Many highly active Chinese herbal monomers (e.g., curcumin, chrysin, TAIII) suffer from poor water solubility, low oral bioavailability, and rapid metabolism in vivo, limiting the full expression of their efficacy. Recent advances in drug delivery systems, including liposomes, polymeric micelles, and mesoporous silica nanoparticles, offer promising strategies to overcome these barriers[85].

Ambiguity of multi-target mechanisms

“Multi-target” is a double-edged sword. The exact primary and secondary targets in vivo, as well as the synergistic/antagonistic relationships between them, remain unclear, making precise risk-benefit assessment difficult. Emerging technologies such as network pharmacology, molecular docking, and multi-omics approaches are beginning to address these challenges[71].

Unknown systemic toxicity and long-term safety

Some Chinese herbal monomers (e.g., TAIII) possess inherent toxicity. Their therapeutic window, organ toxicity, and long-term safety profiles urgently require systematic evaluation[25].

Insufficient clinical evidence

The vast majority of research remains at the preclinical stage. There is a lack of large-scale, well-designed randomized controlled clinical trials to verify the efficacy and safety of these compounds. This highlights the significant gap between promising preclinical results and confirmed clinical efficacy.

CLINICAL TRANSLATION STATUS OF REPRESENTATIVE CHINESE HERBAL MONOMERS

While the preceding sections have repeatedly noted the overall lack of high-quality clinical evidence for Chinese herbal monomers, this subsection systematically examines the translational status of representative anti-HCC monomers that have progressed to clinical testing or real-world medical practice.

FUTURE PERSPECTIVES

To overcome the aforementioned challenges and promote the deepening and translation of anti-HCC research on Chinese herbal monomers, future research can focus on the following directions.

Deepen mechanistic research for precise analysis

Utilize modern technological means such as artificial intelligence, multi-omics technologies (genomics, proteomics, metabolomics), and high-content screening to systematically reveal the precise targets and upstream/downstream signaling events of Chinese herbal monomers within complex biological networks (Figure 3).

Figure 3 Integrative network of multi-target actions of Chinese herbal monomers against hepatocellular carcinoma. It summarizes the core signaling pathways regulated by Chinese herbal monomers and their biological effects, including inhibiting cell proliferation, inducing cell death, suppressing angiogenesis and metastasis, reversing drug resistance, and remodeling tumor immune microenvironment. RAS: Rat sarcoma virus; RAF: Rapidly accelerated fibrosarcoma; MEK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinases; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; IL-6: Interleukin-6; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; INF-α: Interferon-alpha; IKK: I kappa B kinase; NF-κB: Nuclear factor-kappa B; IκB: I kappa B; MAPK: Mitogen-activated protein kinases.

Strengthen structural optimization to improve druggability

Based on the initially established structure-activity relationships, perform rational structural modification and optimization on high-activity lead compounds. Simultaneously, actively develop novel drug delivery systems (e.g., nanoparticles, liposomes, polymeric micelles) to enhance targeted drug delivery efficiency and bioavailability[24,85].

Explore combination therapies to leverage synergistic advantages

Focus on conducting combination therapy research between Chinese herbal monomers and existing standard treatments (e.g., sorafenib, lenvatinib, programmed cell death-1/PD-L1 inhibitors), seeking optimized regimens for synergistic enhancement and reversal of chemotherapy resistance[60,73].

Promote clinical translation and accumulate evidence

Actively promote well-designed phase I/II clinical trials to preliminarily evaluate the safety, pharmacokinetic characteristics, and initial efficacy of promising Chinese herbal monomers in HCC patients. Based on this, conduct confirmatory phase III clinical trials.

Expand treatment dimensions, focusing on mind-body integrative therapy

Future research should pay special attention to Chinese herbal monomers for HCC patients with psychological stress, as exemplified by paeoniflorin’s anti-depressant and anti-tumor dual activities[28].

CONCLUSION

In conclusion, Chinese herbal monomers constitute a rich and pharmacologically diverse resource for HCC drug discovery. Their multi-target mechanisms offer a distinct advantage in addressing the complexity of hepatocarcinogenesis and therapeutic resistance. This review provides a systematic structural classification and a preliminary structure-class-mechanism association, laying a theoretical foundation for future development. Recent advances in understanding novel cell death mechanisms (ferroptosis, cuproptosis, pyroptosis), immunomodulation, and drug delivery systems have significantly enriched this field. However, our critical analysis reveals that the majority of studies remain at the preclinical stage, with many relying on a limited panel of cell lines and subcutaneous xenograft models. Successful translation will require overcoming significant hurdles in pharmacokinetics, safety, and clinical proof-of-concept, and future research should prioritize the use of clinically relevant models (orthotopic, PDX, genetically engineered mouse models) and rigorous clinical trial design. Through interdisciplinary collaboration – integrating mechanistic research, pharmaceutical engineering, combinatorial therapeutics, and evidence-based clinical evaluation – these natural compounds hold strong potential to evolve into next-generation, clinically validated anti-HCC agents, offering renewed hope for improved patient outcomes.