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

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.

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.