Biosynthesis-guided classification of Hirsutane sesquiterpenoids and their structural diversification

Hirsutane-type sesquiterpenoids are a distinctive class of fungal natural products characterized by a compact linear triquinane (5/5/5) scaffold. First reported in 1947, this family has expanded to structurally diverse metabolites exhibiting cytotoxic, antimicrobial, and anti-inflammatory activities. Recent advances in genome mining and enzymatic characterization have revealed that hirsutane diversification is governed by a coherent biosynthetic logic, in which a dual-domain sesquiterpene synthase and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase fusion enzyme constructs the core scaffold, followed by regioselective A-ring oxidation and late-stage tailoring reactions. In this review, we summarize 131 natural hirsutane derivatives reported up to early 2026 and reorganize them within a biosynthesis-guided classification framework. Based on A-ring modification patterns, these compounds are classified into three major biogenetic lineages (G1-G3) and further subdivided into 14 subclasses, providing a systematic view of their oxidative diversification pathways. This biosynthetic framework facilitates comparative analysis of biological activities and indicates that progressive A-ring oxidation generally correlates with enhanced bioactivity. Overall, this review integrates biosynthetic mechanisms with structural organization and offers a chemically intuitive basis for future discovery and engineering of hirsutane-based bioactive molecules.