Metabolic Competition between Non-reducing Polyketide Synthases Drives Hidden Chemodiversity in Deep-Sea Fungus Talaromyces radicus

Genome mining of Talaromyces radicus WHUF04045 identified two unusual nrPKSs ( Tr4942 and Tr2381 ) with distinct release mechanisms, whose precursor competition was revealed by multiomics, gene deletion, and heterologous expression. Deletion of Tr4942 activated nine new chromone derivatives ( 1 – 9 ) and four new naphthoquinone derivatives ( 11 – 14 ), which displayed significant pro-angiogenic and anti-inflammatory activities, with compound 8 showing significant anti-inflammatory effects via modulation of the NF-κB signaling pathway.