Article

Translational Potentials of Silymarin: A Comprehensive Narrative Review of Chemistry and Pharmacology

Joseph O.T Emudainohwo, Frank Samuel, Benneth Ben-Azu, Israel O Bolanle, Raymond I Ozolua

Background and Purpose: Silymarin, a flavonolignan complex derived from Silybum marianum (L.) Gaertn. (milk thistle), has been extensively studied for its therapeutic potential in metabolic, neuropsychiatric, and neurodegenerative diseases. Despite over four decades of research and more than 12,000 PubMed-archived records on Silybum marianum and its constituents, of which over 3,000 relate specifically to silymarin and its flavonolignans, existing reviews predominantly focus on specific disease states, often overlooking the comprehensive structure-activity relationships and mechanistic foundations. This comprehensive narrative review provides an integrated, up-to-date analysis of silymarin’s chemistry, pharmacological actions, underlying mechanisms, and translational potential.

Methods: This involved a comprehensive narrative review rather than a systematic review. We identified relevant articles published between 1981 and 2026 through PubMed, Scopus, and Google Scholar using keywords related to silymarin, flavonolignans, pharmacological actions, mechanisms, and clinical applications, supplemented by hand-searching reference lists. We selected articles for relevance and quality without a pre-registered protocol, standardized Boolean strings, predefined inclusion criteria, formal risk-of-bias assessment, or PRISMA reporting.

Results: The literature demonstrates that silymarin exerts multifaceted pharmacological effects, including hepatoprotective, anticancer, cardioprotective, neuroprotective, and immunomodulatory activities. These actions are mediated by integrated mechanistic pathways: Nrf2-driven antioxidant defense, NF-?B/NLRP3 anti-inflammatory signaling, mitochondrial protection, upregulation of neurotrophic factors (BDNF/GDNF), and modulation of cholinergic and monoaminergic systems. Structure-activity relationship analysis reveals that the flavonolignan scaffold, particularly the phenolic hydroxyl groups and 1,4-benzodioxane ring system, underlies these diverse activities. Notable translational challenges, such as poor oral bioavailability, are being addressed through advanced formulation strategies, including liposomes, nanoemulsions, and phytosomes.

Conclusion: Silymarin has evolved beyond traditional hepatoprotection and shows therapeutic potential across diverse diseases. While preclinical evidence is compelling, well-designed randomized controlled trials are needed to validate clinical utility and optimize therapeutic applications. Integrating novel formulations with mechanistic understanding holds promise for translating silymarin's potential into clinical practice.