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

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.