In the realm of natural medicine, a potent compound hidden within the sweet veins of licorice root is quietly revolutionizing how we approach healing, from fighting viruses to targeting cancer cells.
Imagine a natural substance so versatile it can calm an upset stomach, fight viruses, and even help deliver cancer medication directly to tumor cells. This isn't a futuristic drug design; it's the remarkable power of glycyrrhetinic acid (GA), the active compound that gives licorice root its therapeutic potency and characteristic sweetness.
For centuries, licorice has been revered in traditional medicine systems, first recorded in the Eastern Han Dynasty in China where it was honored as the "lord of all medicines" for its ability to harmonize different drug formulations 3 .
Today, modern science is uncovering the secrets behind its healing power, revealing that glycyrrhetinic acid operates at a sophisticated molecular level, offering exciting possibilities for modern medicine.
Glycyrrhetinic acid is the active metabolic component that results when our bodies process glycyrrhizic acid, the main triterpenoid saponin in licorice root 3 . Think of glycyrrhizic acid as the complete package—one molecule of GA coupled with two molecules of glucuronic acid 3 . When this compound enters the body, enzymes cleave it to release GA, which is primarily responsible for the celebrated pharmacological effects.
The global market for this potent compound is expanding rapidly, projected to grow from $250 million in 2024 to $450 million by 2033 1 .
Recent research has revealed GA's impressive antiviral capabilities, particularly in the context of COVID-19. The SARS-CoV-2 main protease (Mpro) is an essential enzyme for viral replication and represents an attractive drug target because it has no human equivalents 2 .
GA can block viral entry by inhibiting the interaction between the spike protein and ACE2 receptor 2 .
GA suppresses viral replication by inhibiting Mpro 2 .
Scientists have created glycosylated derivatives of GA by attaching sugar molecules to enhance its drug-like properties. These modified compounds, particularly 18β-GA-3-O-β-Glc and 18β-GA-30-O-β-Glc, have shown promising results against SARS-CoV-2 2 .
| Compound Name | IC50 Value (μM) | Significance |
|---|---|---|
| 18β-GA-30-O-β-Glc | 4.77 ± 0.49 | Most potent inhibitor |
| 18β-GA-3-O-β-Glc | 8.70 ± 0.80 | Strong inhibition |
| Parent GA Compound | Not reported | Less effective than derivatives |
GA's antitumor mechanisms are equally impressive, working through several coordinated approaches:
Inducing autophagy and cell death in cancer cells 4 .
Altering key signaling pathways including ERK, TGF-β/Smad, and PI3K/AKT 4 .
Enhancing response of type I interferon in innate immune cells 4 .
GA demonstrates synergistic effects when combined with conventional chemotherapy drugs like doxorubicin and 5-fluorouracil, enhancing their efficacy while potentially reducing adverse reactions 4 .
GA's benefits extend beyond human medicine into veterinary science. A 2025 study investigated its protective effects against zearalenone (ZEN), a mycotoxin that causes serious reproductive harm in animals, particularly replacement gilts (young female pigs) 5 .
GA alleviates ZEN-induced reproductive toxicity by modulating endocrine and hepatic metabolic pathways 5 , demonstrating its potential as a natural protective agent in agriculture.
Despite its impressive therapeutic potential, GA faces a significant limitation: poor water solubility 7 , which reduces its bioavailability—the amount of drug that actually reaches circulation to exert its effects.
To address this, pharmaceutical scientists have developed innovative formulation strategies, particularly ternary solid dispersion (TSD) systems incorporating alkalizers like L-arginine and meglumine 7 .
A groundbreaking study published in 2025 developed a sophisticated method to create glycosylated GA derivatives with improved properties 2 .
The system included N-acetylhexosamine 1-kinase (NahK), UDP-sugar pyrophosphorylase (BLUSP), inorganic pyrophosphorylase (PmPpA), and a GT-B type NDP-glycosyltransferase (Bs-YjiC) 2 .
This innovative approach eliminated the need for costly UDP-sugar precursors, significantly reducing production costs while generating nine distinct GA glycosides 2 .
The glycosylated derivatives showed markedly improved antiviral activity compared to standard GA.
The enhanced performance stems from improved binding to the viral protease. Molecular docking studies revealed that these glycosides establish stable binding conformations similar to GC376, a well-known protease inhibitor 2 .
| Derivative Number | Compound Name | Sugar Component | Type |
|---|---|---|---|
| 3 | 18β-GA-3-O-β-Glc | Glucose | Mono-glycoside |
| 4 | 18β-GA-30-O-β-Glc | Glucose | Mono-glycoside |
| 5 | 18β-GA-3,30-O-β-bis-Glc | Glucose | Di-glycoside |
| 6 | 18β-GA-3-O-β-Man | Mannose | Mono-glycoside |
| 7 | 18β-GA-30-O-β-Man | Mannose | Mono-glycoside |
| 8 | 18β-GA-3,30-O-β-bis-Man | Mannose | Di-glycoside |
| 9 | 18β-GA-30-O-β-Gal | Galactose | Mono-glycoside |
| 10 | 18β-GA-3-O-β-2-DG | 2-deoxyglucose | Mono-glycoside |
| 11 | 18β-GA-3-O-β-2-DGal | 2-deoxygalactose | Mono-glycoside |
Studying and utilizing GA requires specialized materials and methods. The following table highlights essential reagents and their applications in GA research.
| Reagent/Category | Specific Examples | Function/Application |
|---|---|---|
| Extraction Solvents | Ethanol, methanol | Isolate GA from licorice root |
| Analytical Standards | Pure GA (≥98% purity) | Quality control and quantification |
| Cell Culture Models | Hepatocyte cells, cancer cell lines | Study antitumor and liver-protective mechanisms |
| Animal Models | Wistar rats, mouse tumor models | Investigate in vivo efficacy and toxicity |
| Formulation Polymers | Kollidon® VA64, Soluplus, Poloxamers | Enhance solubility via solid dispersions |
| Alkalizers | L-arginine, meglumine, Mg(OH)₂, Na₂CO₃ | Improve dissolution of weakly acidic GA |
| Nanocarrier Systems | Alginate nanoparticles, hyaluronic acid nanoparticles | Targeted drug delivery, especially to liver |
As research progresses, GA continues to reveal new therapeutic dimensions. Nanotechnology approaches are creating exciting opportunities, with GA nanoparticles demonstrating superior gastroprotective effects in animal models—outperforming even the conventional drug omeprazole in protecting against ethanol-induced gastric ulcers .
The unique property of GA to bind specifically to receptors on hepatocytes (liver cells) makes it particularly valuable for targeted drug delivery 3 . By attaching GA to drug carriers or even directly to medications, researchers can create "homing devices" that deliver therapeutics directly to liver cells.
Developing more efficient nanocarriers and formulation strategies to enhance bioavailability.
Exploring combinations with other therapeutic modalities like immunotherapy and gene therapy.
Conducting rigorous clinical trials to translate promising findings into real-world treatments.
Glycyrrhetinic acid exemplifies the enduring power of nature's pharmacy and the importance of investigating traditional remedies through the lens of modern science. From its humble origins in licorice root to its sophisticated applications in targeted drug delivery and antiviral therapy, GA's journey reflects the evolution of medicine itself.
As research continues to unravel its complexities, this ancient compound continues to offer new solutions to contemporary health challenges, reminding us that sometimes the most advanced medicines can be found not in synthetic laboratories, but in the intricate chemistry of plants that have healed for millennia. The future of GA research holds the promise of harnessing nature's wisdom with precision science to develop more effective, targeted, and gentle therapies for some of medicine's most persistent challenges.