Ergosterol: Biological Activities, Mechanistic Evidence, Pharmacokinetic Barriers, and Delivery Strategies

Ergosterol is a fungal sterol with broad pharmacological activities, including anticancer, anti-inflammatory, cholesterol- and uric acid-lowering effects, and serves as the precursor of vitamin D₂. Despite its therapeutic potential, poor aqueous solubility, physicochemical instability, and low oral bioavailability severely limit its clinical application. This review provides an integrative overview of the physicochemical properties, biosynthesis, biological activities, underlying molecular mechanisms, pharmacokinetics, and safety profiles of ergosterol and its major derivatives. A structured literature search was conducted in PubMed, Web of Science, Scopus and CNKI up to February 2026, with findings critically synthesized across preclinical models. Current evidence links ergosterol-related interventions to changes in signaling pathways such as PI3K/Akt, NF-κB, and Wnt/β-catenin, although direct target-engagement evidence remains limited for many disease models. The review concludes that while ergosterol represents a promising natural scaffold for drug development, translational progress is constrained by limited human pharmacokinetic data and insufficient exposure-response validation. Future research should prioritize metabolite profiling, clinically relevant dosing strategies, and formulation optimization to better define the translational potential of ergosterol-based compounds.