Recent progress in macrocyclic trichothecene research: structures, biosynthetic pathways, and biological activities

Macrocyclic trichothecenes are a distinctive class of secondary metabolites produced by Ascomycota characterized by complex macrocyclic scaffolds and diverse biological activities, including antibacterial, antitumor, and immunomodulatory effects. This review provides a comprehensive summary of their classification, biosynthetic pathways, and bioactivities, with a particular focus on research advances from 2015 to 2025. During this period, 30 new macrocyclic trichothecene derivatives have been identified from fungal genera such as Myrothecium, Podostroma, Stachybotrys, Fusarium, and Paramyrothecium. Their biosynthesis is primarily governed by polyketide synthase (PKS) and terpene synthase systems, with key genes such as TRI5 and TRI4 playing central roles. Structural features—including epoxy moieties and side-chain modifications—have been shown to significantly influence their biological activities. In this review, we emphasize newly discovered compounds and recent insights into their biosynthetic mechanisms as well as the anticancer capabilities of different compounds, aiming to provide a valuable reference for future research on the development, optimization, and application of macrocyclic trichothecene derivatives in medical and agricultural contexts.