Multi-Target Hepatoprotective Mechanisms of Glycyrrhiza glabra: Molecular Pathways, Experimental Evidence, and Clinical Translation

Abstract

Background: Liver diseases including non-alcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, cholestatic injury, and fibrosis are driven by interconnected mechanisms such as oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, and dysregulated lipid metabolism. Glycyrrhiza glabra has long been used in traditional medicine and contains multiple bioactive compounds with potential hepatoprotective activity. Objective: To critically synthesize the phytochemical basis, molecular pathways, experimental evidence, and clinical translational relevance of Glycyrrhiza glabra in liver protection. Methods: A structured narrative review was conducted using literature from major biomedical databases and reference screening, with emphasis on liver-specific studies evaluating extracts, isolated constituents, and derivatives of Glycyrrhiza glabra. Evidence was organized by phytochemistry, molecular mechanisms, preclinical hepatoprotective models, and clinical relevance. Results: The strongest evidence supports antioxidant and anti-inflammatory effects mediated through Nrf2 activation, NF-κB suppression, modulation of Bax/Bcl-2 and caspase signaling, inhibition of CYP2E1-related toxic bioactivation, and partial attenuation of TGF-β1-associated fibrogenesis. Glycyrrhizin, 18β-glycyrrhetinic acid, glabridin, liquiritigenin, isoliquiritigenin, and magnesium isoglycyrrhizinate were the principal compounds linked to hepatoprotection. Experimental studies consistently reported reductions in ALT, AST, ALP, malondialdehyde, and inflammatory cytokines with restoration of endogenous antioxidant defenses and histological improvement. Clinical evidence suggests biochemical benefit in selected liver disorders, but remains heterogeneous. Conclusion: Glycyrrhiza glabra is a promising multi-target hepatoprotective agent, although clinical translation requires standardized formulations, pharmacokinetic optimization, safety monitoring, and well-designed randomized trials.