Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications
Abstract
1. Introduction
2. Chemical Structures and Pharmacological Properties
2.1. Structure, Biosynthesis, and Production
2.1.1. Classification and Basic Structures
2.1.2. Formation Pathways and Production Technologies
2.1.3. Production Technologies
2.1.4. Structure–Function Relationships
2.2. SAR for Immunomodulation
2.2.1. Sugar Position and Immune Activity
2.2.2. Anti-Inflammatory Mechanisms and Sugar Moiety Effects
2.2.3. Stereochemistry and Biological Activity
2.2.4. Molecular Weight and Membrane Permeability
2.2.5. Receptor Interactions and Signal Transduction
2.2.6. Structure-Based Design Implications
3. Individual Ginsenoside Profiles: Unique Immunomodulatory Mechanisms
3.1. Ginsenoside F1: The Exceptional Immune Enhancer
3.1.1. Unique Immunostimulatory Profile Among Rare Ginsenosides
3.1.2. NK Cell Activation Mechanisms
3.1.3. In Vivo Efficacy in Cancer and Inflammatory Models
3.1.4. Bioavailability Enhancement and Clinical Applications
3.2. Ginsenoside Rg5: Direct TLR4 Antagonist
3.2.1. TLR4-Mediated Anti-Inflammatory Mechanisms
3.2.2. HMGB1-Mediated Septic Response Inhibition
3.2.3. Synergistic Anti-Inflammatory Effects
3.2.4. Additional Activities and Clinical Translation
3.3. Ginsenoside Rk1: Multi-Pathway Modulator
3.3.1. Broadest Pathway Coverage Among Rare Ginsenosides
3.3.2. Triple Pathway Inhibition: NF-κB, p38 MAPK, and STAT Signaling
3.3.3. Additional Therapeutic Targets
3.3.4. Clinical Development and Combination Strategies
3.4. Ginsenoside Rh1: Anti-Allergic Specialist
3.4.1. Unique Anti-Allergic Profile Among Rare Ginsenosides
3.4.2. Mast Cell Stabilization and Histamine Release Inhibition
3.4.3. Modulation of Th2-Mediated Allergic Responses
3.4.4. Pharmaceutical Optimization and Safety Profile
3.5. Ginsenoside Rg2: Dual-Compartment Immunomodulator
3.5.1. Neuroprotective Mechanisms in Central Nervous System
3.5.2. Peripheral Organ Protection and Systemic Therapeutic Effects
3.5.3. Anti-Inflammatory and Immune Modulation
3.5.4. Clinical Translation Potential and Safety Profile
4. Comparative Analysis and SAR
4.1. Standardized Indirect Comparison
4.2. Mechanistic Pathway Mapping
4.3. Structural and Mechanistic Basis for F1’s Unique Immunostimulatory Activity
5. Cancer Immunotherapy Applications
5.1. F1: Multitarget Anticancer Mechanisms
5.2. Rk1’s Multifaceted Anticancer Mechanisms
5.3. Strategic Combination Approaches for Ginsenoside-Based Cancer Therapy
6. Applications in Inflammatory and Autoimmune Diseases
6.1. Allergic Diseases—Rh1 Dominance
6.1.1. Mechanisms of Anti-Allergic Action
6.1.2. Disease Model Efficacy
6.2. Inflammatory Disease—Rk1’s Intestinal Focus
6.2.1. Anti-Inflammatory Mechanisms
6.2.2. Barrier Function Restoration
6.3. Sepsis—Individual Mechanisms
6.4. Synergistic Effects and Combination Strategies
7. From Bench to Bedside: Translational Challenges and Opportunities
7.1. Current Translational Status
7.2. Pharmacokinetic Challenges and Solutions
7.3. Critical Assessment of Delivery Systems: Benefits, Limitations, and Enhancement Strategies
7.4. Pharmaceutical Applications and Safety Profiles
7.5. Future Opportunities and Perspectives
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
25-OCH3-PPD | 25-methoxy-protopanaxadiol |
A20 | Tumor necrosis factor-α-induced protein 3 |
AA | Arachidonic acid |
AGS-H | Heat-processed American ginseng saponins |
ALT | Alanine aminotransferase |
AMPK | AMP-activated protein kinase |
AP-1 | Activator protein-1 |
ApoE | Apolipoprotein E |
APPswe | Amyloid precursor protein Swedish mutation |
ARE | Antioxidant response element |
ASC | Apoptosis-associated speck-like protein containing a caspase recruitment domain |
AST | Aspartate aminotransferase |
ATP | Adenosine triphosphate |
Bax | Bcl-2-associated x protein |
Bcl-2 | B-cell lymphoma 2 |
BDNF | Brain-derived neurotrophic factor |
BMP-2 | Bone morphogenetic protein-2 |
Brn-3a | Brain-specific homeobox/POU domain protein 3a |
BUN | Blood urea nitrogen |
C17SCV | C17 side-chain varied |
cAMP | cyclic adenosine monophosphate |
CD | Cluster of differentiation |
c-Fos | c-Fos proto-oncogene |
c-Jun | Cellular Jun proto-oncogen |
c-Myc | Cellular myelocytomatosis oncogene |
COL1A1 | Collagen type I alpha 1 |
COVID-19 | Coronavirus disease 2019 |
COX | Cyclooxygenase |
cPLA2 | Cytosolic phospholipase A2 |
CREB | cyclic adenosine monophosphate response element-binding protein |
CYP3A4 | Cytochrome P450 3A4 |
CYP450 | Cytochrome P450 |
EC50 | Half maximal effective concentration |
EGCG | Epigallocatechin-3-gallate |
EMT | Epithelial to mesenchymal transition |
eNOS | Endothelial nitric oxide synthase |
ER | Endoplasmic reticulum |
Egr-1 | Early growth response 1 |
ERK | Extracellular signal-regulated kinase |
FDA | Food and Drug Administration |
Foxp3 | Forkhead box P3 |
FUNDC1 | FUN14 domain containing 1 |
GABA | Gamma-aminobutyric acid |
G-CSF | Granulocyte colony-stimulating factor |
GLS1 | Glutaminase 1 |
Glu | Glutamate |
GLUT1 | Glucose transporter 1 |
GM1 | Monosialotetrahexosylganglioside 1 |
GRAS | Generally recognized as safe |
GSH | Glutathione |
GTPase | Guanosine triphosphatase |
GZMB | Granzyme B |
HaCaT | Human keratinocyte |
HDAC2 | Histone deacetylase 2 |
HMGB1 | High mobility group box 1 |
HO | Heme oxygenase |
hP2X7 | Human P2X purinoceptor 7 |
HSP70 | Heat shock protein 70 |
IBD | Inflammatory bowel disease |
IC50 | Half maximal inhibitory concentration |
ICAM-1 | Intercellular adhesion molecule-1 |
ICU | Intensive care unit |
IDE | Insulin-degrading enzyme |
IFN-γ | Interferon-gamma |
Ig | Immunoglobulin |
IGF-1 | Insulin-like growth factor-1 |
IGF-1R | Insulin-like growth factor-1 receptor |
IκBα | Inhibitor of nuclear factor kappa b alpha |
IKKβ | Inhibitor of nuclear factor kappa b kinase subunit beta |
IL | Interleukin |
iNOS | Inducible nitric oxide synthase |
JAK | Janus kinase |
JNK | c-Jun N-terminal kinase |
LOX-1 | Lectin-like oxidized low-density lipoprotein receptor-1 |
LPS | Lipopolysaccharide |
MAPK | Mitogen-activated protein kinase |
MCP-1 | Monocyte chemoattractant protein-1 |
MD2 | Myeloid differentiation factor 2 |
MDA | Malondialdehyde |
MI/R | Myocardial ischemia/reperfusion |
MIP-1δ | Macrophage inflammatory protein-1 delta |
MMP | Matrix metalloproteinase |
MPTP | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
MRL/lpr | Murphy Roths Large/lymphoproliferation |
mTOR | Mammalian target of rapamycin |
MW | Molecular weight |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NEP | Neprilysin |
NETosis | neutrophil extracellular traps formation |
NeuN | Neuronal nuclei |
NFATc1 | Nuclear factor of activated T-cells, cytoplasmic 1 |
NF-κB | Nuclear factor-kappa B |
NGAL | Neutrophil gelatinase-associated lipocalin |
NGF | Nerve growth factor |
NK | Natural killer |
NKG2D | Natural killer group 2 member D |
NLC | Nanostructured lipid carrier |
NLRP3 | Nucleotide-binding oligomerization domain-like receptor protein 3 |
NMDA | N-methyl-D-aspartate |
NOX1 | Nicotinamide adenine dinucleotide phosphate oxidase 1 |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
OA | Oleanolic acid |
p-ACC | Phosphoacetyl-CoA carboxylase |
PAM | Positive allosteric modulator |
PCA | Passive cutaneous anaphylaxis |
PD-L1 | Programmed death-ligand 1 |
PEGylated | Polyethylene glycol-conjugated |
PGE | Prostaglandin E |
P-gp | P-glycoprotein |
PI3K/AKT | Phosphatidylinositol 3-kinase/protein kinase B |
PKC | Protein kinase C |
PKCδ | Protein kinase C delta |
PLA2 | Phospholipase A2 |
PLCγ | Phospholipase Cγ |
PLD | Phospholipase D |
PPD | Protopanaxadiol |
PPT | Protopanaxatriol |
PSEFS | Peanut sprout extracts cultivated with fermented sawdust medium |
PSEN1dE9 | presenilin 1 deletion of exon 9 |
RANKL | Receptor activator of nuclear factor kappa-B ligand |
RC50 | Half maximal response concentration |
Rho | Ras homolog |
RIP | Receptor-interacting protein |
ROS | Reactive oxygen species |
Runx2 | Runt-related transcription factor 2 |
SAR | Structure–activity relationship |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
SIRT1 | Sirtuin 1 |
Smad | Smad family proteins |
SMEDDS | Self-microemulsifying drug delivery systems |
SOD | Superoxide dismutase |
STAT | Signal transducer and activator of transcription |
Syk | Spleen tyrosine kinase |
TAK1 | Transforming growth factor-beta-activated kinase 1 |
t-BHP | Tertiary-butyl hydroperoxide |
TGF-β1 | Transforming growth factor-β1 |
Th | T helper |
TLR4 | Toll-like receptor 4 |
TME | Tumor microenvironment |
TNBS | Trinitrobenzenesulfonic acid |
TNF-α | Tumor necrosis factor alpha |
ULK1 | Unc-51 like autophagy activating kinase 1 |
UVB | Ultraviolet B |
VEGF | Vascular endothelial growth factor |
ZO-1 | Zonula occludens-1 |
α-MSH | Alpha-melanocyte stimulating hormone |
α-SMA | Alpha-smooth muscle actin |
γδ T cells | Epidermal gamma delta T cells |
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Ginsenoside | Type | Key Immunomodulatory Effects | Main Mechanisms | Ref. |
---|---|---|---|---|
F1 | PPT |
|
| [25,27,63] |
Rg5 | PPD |
|
| [64,65] |
Rk1 | PPD |
|
| [66] |
Rh1 | PPT |
|
| [41,42] |
Rg2 | PPT |
|
| [42,67] |
Ginsenoside | Primary Effect | Key Mechanisms | Target Diseases | Ref. |
---|---|---|---|---|
F1 | Immunostimulation |
|
| [25,63] |
Rg5 | Anti-inflammation |
|
| [66,103] |
Rk1 | Multi-pathway inhibition |
|
| [66,117] |
Rh1 | Anti-allergic |
|
| [42,130] |
Rg2 | Neuroimmune regulation |
|
| [42,162] |
Model | Ginsenoside | Dose | Route | Duration | Key Outcome | Ref. |
---|---|---|---|---|---|---|
Cancer models | ||||||
CT26 colon cancer (mice) | F1 | 20 mg/kg | i.p. | 14 days | 67% tumor growth inhibition | [25] |
RMA-s lymphoma (mice) | F1 | 25–50 mg/kg | i.p. | 3 days pretreatment | 70% rejection vs. 20% control at 6 h | [25] |
B16F10 melanoma (mice) | F1 | 50 mg/kg | i.p. | 3 days pre + 3×/week | Reduced lung metastases | [25] |
Sepsis models | ||||||
CLP-induced sepsis (mice) | Rg5/Rk1 | 0.061 mg/kg | i.v. | 12 h & 50 h post-CLP | 70% survival vs. 20% control | [66] |
HMGB1-induced sepsis (mice) | Rg5/Rk1 | 0.031–0.061 mg/kg | i.v. | Single | Reduced HMGB1, TNF-α, IL-6 | [66] |
Inflammatory models | ||||||
LPS-induced inflammation (mice) | Rg2/Rh1 | Not specified | Not specified | Not specified | Synergistic reduction in liver/kidney damage | [42] |
CIA (mice) | Rh1 + DEX | 10 mg/kg (Rh1) + 1 mg/kg (DEX) | i.p. | 10 days | Enhanced anti-inflammatory effects vs. DEX alone | [130] |
Neurological models | ||||||
MCAO stroke (rats) | F1 | 50 mg/kg | p.o. | 14 days | Increased MVD, improved cerebral perfusion | [26] |
Sleep deprivation (mice) | Rg5/Rk1 | 30–60 mg/kg | p.o. | 7 days | Increased sleep duration, reduced latency | [99] |
Ginsenoside | Species /Model | Bioavailability /PK Parameters | Enhancement Strategy | Improved Outcome | Ref |
---|---|---|---|---|---|
F1 | Caco-2 cells | <5% (estimated); 26.0% permeability | Nanostructured lipid carrier | 39.2% permeability; 90% encapsulation | [85] |
Rat (as Rg1 metabolite) | Detected in feces (parent Rg1: 40.11%) | – | – | [83] | |
Rg5 | In vitro | Low | Cyclodextrin complexation | 1.8-fold increase | [121] |
Zebrafish | Low; 7 metabolites identified | – | – | [218] | |
Rk1 | In vivo | <3% oral absorption | Liposome (97.24% encapsulation) | >50% tumor reduction | [117] |
Rat | 2.87–4.23% (T1/2: 3.09–3.40 h) | – | – | [118] | |
Zebrafish | Low; 4 metabolites | – | – | [218] | |
Rh1 | In vitro/rat | 12.92% | SMEDDS | 33.25% (2.6-fold increase) | [139] |
Rat | 1.01% (T1/2β: 0.41 h) | – | – | [220] | |
Rg2 | In vitro | Low | Lipid nanoparticles | Enhanced mRNA delivery (81.9% encapsulation) | [162] |
Rat microsomes | Low; metabolites M1, M3, M4 | – | – | [161] | |
Human plasma | Not detected as parent | – | – | [39] |
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Hong, C.-E.; Lyu, S.-Y. Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications. Pharmaceuticals 2025, 18, 1529. https://doi.org/10.3390/ph18101529
Hong C-E, Lyu S-Y. Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications. Pharmaceuticals. 2025; 18(10):1529. https://doi.org/10.3390/ph18101529
Chicago/Turabian StyleHong, Chang-Eui, and Su-Yun Lyu. 2025. "Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications" Pharmaceuticals 18, no. 10: 1529. https://doi.org/10.3390/ph18101529
APA StyleHong, C.-E., & Lyu, S.-Y. (2025). Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications. Pharmaceuticals, 18(10), 1529. https://doi.org/10.3390/ph18101529