Preclinical ginsenoside evidence points to multiple liver-cancer mechanisms

A review of 86 studies reports that ginsenosides, natural triterpenoid saponins obtained from several Panax species, suppress liver-cancer growth, invasion and tumor-associated signaling in cellular and animal models. The evidence is strongest as a collection of experimental observations rather than as proof of a single mechanism: compounds including Rh2 and Rg3 were reported to influence programmed cell death, oxidative stress, autophagy, cell-cycle control, metabolism and immune regulation. Most mechanistic findings came from cultured cells or subcutaneous tumors, and the authors cautioned that these models do not fully reproduce the architecture, metabolism or immune environment of an orthotopic liver tumor. Human evidence was more limited and heterogeneous, with a notable randomized trial reporting longer survival when Rg3 was added to transarterial chemoembolization for advanced hepatocellular carcinoma.

The authors searched PubMed and Web of Science from database inception through August 2026, using terms related to ginsenosides and hepatocellular carcinoma alongside mechanism-specific terms. They identified 495 records, screened 338 after removing duplicates and assessed 111 full-text articles; 86 studies entered the qualitative synthesis. No formal risk-of-bias or study-quality assessment was performed because the included work varied substantially in models, dosing regimens, preparations and outcomes, while quantitative pooling of effect sizes was not considered appropriate. Chemically distinct interventions were kept separate: parent ginsenosides were not treated as interchangeable with metabolites such as compound K, processing-derived derivatives, total-ginsenoside preparations or nanoformulations. Studies using hepatoblastoma-derived cells, including HepG2, were treated as supportive liver-tumor evidence with limited transferability to established hepatocellular carcinoma.

At the cellular level, one recurring theme was mitochondrial destabilization followed by caspase-dependent apoptosis. In Hep3B cells, Korean red ginseng extract and its major constituents Rg3 and Rh2 increased intracellular reactive oxygen species, reduced mitochondrial membrane potential and promoted cytochrome c release, increased Bax expression and caspase-3 activation. Other experiments linked Rh2 treatment to Bax and Bak translocation, while compound K was associated with mitochondrial depolarization, DNA damage, changes in Fas and Fas ligand signaling, and a higher Bax-to-Bcl-2 ratio. Protopanaxadiol supplied another route to cell death by inducing endoplasmic reticulum stress, PERK/eIF2α phosphorylation, XBP1 splicing and activation of death-receptor and caspase pathways. Compound K was reported to increase this response when phosphorylated STAT3 was suppressed. These observations describe mechanisms observed in experimental systems and do not establish that the same sequence occurs in patients.

Autophagy produced mixed results that depended on the compound and experimental context. Rk1 induced early autophagy that appeared to protect tumor cells: pharmacological blockade or genetic silencing of autophagy increased Rk1’s antitumor effect. In a separate primary liver-cancer model, however, Rk1 activated AMPK, suppressed mTOR and increased LC3-II in association with apoptosis, consistent with an autophagy-linked death response. Rh2 promoted autophagy while inhibiting β-catenin signaling, and interference with Atg7 or β-catenin removed the reported effect. Rg3 took a different route by blocking late-stage autophagic flux, preventing the protective autophagy induced by doxorubicin and improving the drug’s effect in xenograft models. The divergent findings mean that “autophagy modulation” cannot be assumed to have the same biological meaning or therapeutic consequence for every ginsenoside or experimental setting.

Several studies linked ginsenosides with changes in the energy and materials needed for tumor growth. Rg3 was associated with increased miR-139-5p, reduced expression of its target AURKA, lower levels of the glucose transporters GLUT1 and GLUT4, and diminished lactate and glucose output in transplanted tumors. Under hypoxic conditions, compound K was reported to suppress HIF-1α-associated glycolysis, reduce ATP production and glucose uptake, and restrain liver-cancer cell proliferation. Other experiments linked compound K to lower HK2 and PKM2 abundance through AKT/mTOR/c-Myc signaling. A regimen combining Rg3 with cantharidin was associated with changes in lipid metabolism involving PRMT1 and SREBF1, but that observation applies to the tested combination and cannot be attributed to free Rg3 alone. These findings suggest multiple metabolic routes in models, rather than a clinically established metabolic target.

Transcriptional and epigenetic regulation provided additional links between ginsenosides and reduced proliferation. In HepG2 cells, Rh2 increased miR-146a-5p, and experimentally increasing or inhibiting that microRNA correspondingly strengthened or weakened effects on survival and colony formation. Rh2 was also reported to increase miR-491, which represses EGFR translation, while transcriptomic analysis of treated cells pointed toward p53 signaling and DNA-replication networks. Separate work found that 20S-Rg3 reduced global and promoter-region DNA methylation alongside DNMT3a and DNMT3b expression. Cell-cycle experiments identified G0/G1 or G1/S arrest in response to several compounds: Rs4 increased p53 and p21WAF1 while reducing cyclin E and cyclin A activity, and Rg5 increased p21Cip1/WAF1 while lowering CDK2 and CDC25A. The response was not uniform, because Rg1 was reported to increase cyclin E–CDK2 activity and proliferation in the same hepatoma context.

More recent model-based evidence implicated ferroptosis, an iron-dependent form of regulated cell death associated with lipid peroxidation, glutathione depletion and increased iron. Rk1 was reported to lower glutathione and raise malondialdehyde and iron levels in HepG2 cells, with ferroptosis inhibitors substantially rescuing the phenotype and genetic evidence implicating FSP1. Rg1 was associated with reduced expression of the cystine transporter SLC7A11, while compound K was linked to diminished FOXO1 phosphorylation and lower SLC7A11 and GPX4 expression. The protopanaxatriol derivative 20S-APPT was reported to target FSP1, an enzyme that normally restrains lipid oxidation, and compound K was associated with OTUB2-mediated degradation of GPX4 in xenograft models. These are mechanistic findings in experimental systems; the review did not establish ferroptosis as an operative mechanism in treated patients.

Some studies also suggested that ginsenosides can modify the inflammatory and immune environment surrounding tumors. Rg3 was reported to reduce intratumoral accumulation of myeloid-derived suppressor cells and alter Kupffer-cell phenotypes in experimental models. In a Hepa1-6/splenocyte co-culture system, Rh2 increased the CD8+ T-cell effector markers CD107a and interferon-gamma while reducing PD-L1/PD-1 signaling, TGF-β1, IL-6, IL-10 and the proportion of regulatory T cells. Rh1 was reported to increase MHC-I expression, dendritic-cell maturation and CD8+ T-cell activation in mouse and ex vivo models, while compound K was associated with EZH2 downregulation and dendritic-cell–NK-cell activity. Because the chemical forms, experimental models and measured endpoints differ, these findings support the possibility of immune modulation without demonstrating equivalent activity across the ginsenoside family or predicting benefit in human tumors.

The clearest clinical signal in the review came from a single-center, open-label randomized trial involving 228 patients with advanced hepatocellular carcinoma, classified as Barcelona Clinic Liver Cancer stage C, with Child–Pugh class A liver function and Eastern Cooperative Oncology Group performance status 0 or 1. Patients were assigned in a 2:1 ratio to transarterial chemoembolization, or TACE, plus oral Rg3 or TACE alone. Of the 228 participants, 152 received the combination and 76 received TACE alone. Median overall survival was 13.2 months with the combination and 10.1 months with TACE alone; the reported hazard ratio was 0.63, with a 95% confidence interval of 0.46 to 0.85 and P = 0.002. Disease control rates were 69.7% and 51.3%, respectively. Constipation was more frequent in the combination group, occurring in 87.5% versus 65.8%, while epistaxis occurred in 5.3% of combination recipients and none of the controls. The open-label design, single-center setting and differences in dosing, schedules, endpoints and safety reporting across randomized studies limit broad generalization.

Delivery systems were proposed as a way to address poor aqueous solubility, limited stability, restricted bioavailability and insufficient tumor exposure. Preclinical formulations include polymer- and lipid-based Rg3 carriers, pH-sensitive Rh2 liposomes, chitosan nanoparticles containing compound K, and systems responsive to acidic or reducing conditions. An Rg3 nanoparticle formulation was associated with improved antitumor activity and survival in animals compared with free Rg3, while chitosan nanoparticles increased compound K’s solubility and cellular uptake in HepG2 cells. Other experiments explored imaging-guided delivery and sonodynamic therapy. The review treated these results as delivery and feasibility evidence, not established clinical benefit, because carrier composition, exposure and long-term toxicology differ across studies. It identified orthotopic and genetically engineered liver-tumor models, standardized pharmacokinetic and pharmacodynamic measurements, pathway-specific causal experiments, adequately powered stratified trials and long-term safety assessment as priorities for determining whether the experimental signals can become reliable treatments for hepatocellular carcinoma.

Subject of Research: Preclinical mechanisms and clinical translation of ginsenosides for hepatocellular carcinoma

Article Title: Ginsenosides in hepatocellular carcinoma: preclinical evidence, mechanisms, and clinical implications

Article References: Yu, C., Zhu, X., Liu, S., Ding, Y., Fu, H., Li, Y., Gai, M., Tan, M., & Zhao, Z. (2026). Ginsenosides in hepatocellular carcinoma: preclinical evidence, mechanisms, and clinical implications. Frontiers in Pharmacology, 17, Article 1973780. https://doi.org/10.3389/fphar.2026.1973780

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1973780

Keywords: hepatocellular carcinoma, ginsenosides, Rh2, Rg3, apoptosis, autophagy, ferroptosis, tumor microenvironment, nanomedicine, transarterial chemoembolization, hepatocellular, carcinoma