Role of the global regulatory factor VeA in Cordyceps militaris and its overexpression combined with tea polyphenols to enhance cordycepin production.

Cordyceps militaris has recently been regarded as a promising chassis for high-value compound production owing to its advantage in liquid fermentation, while further exploration of genetic targets and exogenous effectors is needed to enhance its productivity. This study presents the first demonstration of the global regulatory factor VeA as a key modulator of morphological development, conidiogenesis, and cordycepin biosynthesis in C. militaris. Furthermore, screening of exogenous effectors identified tea polyphenols as potent metabolic enhancers, which, when combined with veA overexpression, increased cordycepin production by 69.2% during liquid fermentation. Transcriptome analysis further revealed that this synergistic enhancement was associated with elevated metabolic fluxes through the pentose phosphate (PP) pathway and the cordycepin biosynthesis module. This study provides a feasible strategy and mechanism insights into the cooperative use of genetic and chemical interventions for optimizing C. militaris platforms.