Beyond antitumor activity and from lichenized fungi: advances in the production, bioactivities, synthesis, and biosynthesis of usnic acid and its structural derivatives

Usnic acid and its structural derivatives are dibenzofuran natural products characterized by a distinctive 6-5-6 tricyclic scaffold. These compounds, isolated from lichenized fungi, non-lichenized fungi, and select higher plants, exhibit a broad spectrum of biological activities, including significant antitumor, antibacterial, antiviral, and anti-inflammatory properties. However, their clinical application is hampered by low natural abundance and pronounced hepatotoxicity. To overcome these limitations, chemical synthesis and structural modification strategies have yielded derivatives with improved therapeutic profiles. Concurrently, the usnic acid biosynthetic gene cluster has been characterized, revealing a biosynthetic pathway that proceeds through the oxidative coupling of methylphloroacetophenone catalyzed by a dedicated polyketide synthase (MPAS), cytochrome P450 (MPAO), and auxiliary modifying enzymes. This genetic blueprint establishes a critical foundation for the development of synthetic biology platforms enabling sustainable production and structural diversification in heterologous hosts. This review systematically summarizes the natural sources, chemistry, synthetic derivatization, and biosynthetic elucidation of usnic acid, while outlining the prospects and current challenges for the sustainable development of this important natural product family.