Integrative review of Epimedium flavonoids in hepatitis and cirrhosis shows preclinical promise but lacks clinical validation.

Hepatitis and cirrhosis constitute a substantial global health burden, with therapeutic options remaining largely confined to antiviral agents and liver transplantation. Traditional Chinese medicine has long employed Epimedium species (Berberidaceae) for hepatoprotective indications, with contemporary investigations identifying prenylated flavonoids—principally icariin and its active metabolite icaritin—as the principal bioactive constituents. This integrative review systematically examined 33 high-impact studies published up to March 2026, selected based on a comprehensive search of PubMed, Web of Science, Scopus, Embase, Cochrane Library, CNKI, Wanfang, and Google Scholar. Included investigations were critically evaluated for mechanistic sophistication, translational validity, methodological rigor, and pharmacokinetic relevance. Preclinical evidence, derived predominantly from toxin-induced (e.g., CCl4, TAA), metabolic, and acute injury models, demonstrates that icaritin exerts consistent anti-fibrotic activity through dual inhibition of HIF-1α and TGF-β/Smad signaling, selective induction of hepatic stellate cell apoptosis, and suppression of angiogenesis via VEGF/VEGFR2 blockade. Immunomodulatory properties observed in preclinical tumor models and early-phase clinical trials in advanced HBV-related hepatocellular carcinoma, encompass reduction of myeloid-derived suppressor cells (-43%), regulatory T cells (-31%), and enhancement of CD8+ T-cell function (+2.8-fold) providing proof-of-concept for immune modulation in an HBV-endemic population. Clinical data in liver disease remain limited to small, non-randomized studies (primarily in HCC), with no phase III trials specifically targeting fibrosis or cirrhosis endpoints. Critical evidence gaps—including the absence of validation in viral hepatitis models, undefined pharmacokinetics in cirrhosis, and lack of drug-drug interaction data with antivirals—currently preclude routine clinical application in hepatitis and cirrhosis. Safety analyses reveal dose-dependent hepatotoxicity at concentrations exceeding 50 μM icaritin and substantial inter-individual variability in gut microbiota-mediated bioactivation. Epimedium flavonoids exhibit multi-target therapeutic potential that bridges traditional botanical medicine and modern pharmacology, though critical translational gaps persist. Future investigations must prioritize phase III fibrosis trials, pharmacokinetic optimization in cirrhotic populations, and comprehensive drug-drug interaction studies with direct-acting antivirals to establish evidence-based clinical protocols.