Cordycepin is the key pharmacologically active compound of Cordyceps militaris, and various fermentation strategies have been developed to increase cordycepin production. This study aimed to investigate the effect of rotenone on cordycepin biosynthesis in submerged fermentation of C. militaris, and also to explore its possible induction mechanisms via multi-omics analysis. Adding 5 mg/L rotenone significantly increased the cordycepin production by 316.09 %, along with mycelial growth inhibition and cell wall destruction. Moreover, transcriptomic analysis and metabolomic analysis revealed the accumulation of cordycepin was promoted by alterations in energy metabolism and amino acid metabolism pathways. Finally, the integration analysis of the two omics confirmed rotenone altered the nucleotide metabolism pathway toward adenosine and up-regulated the cordycepin synthesis genes (cns1-3) to convert adenosine to cordycepin. This work reports, for the first time, rotenone could act as an effective inducer of cordycepin synthesis.

虫草素是蛹虫草的关键药理活性化合物，已经开发了多种发酵策略来增加虫草素的产量。本研究旨在探讨鱼藤酮对蛹虫草深层发酵中虫草素生物合成的影响。, 并通过多组学分析探索其可能的诱导机制。添加 5 mg/L 鱼藤酮可显着提高虫草素产量 316.09 %，同时抑制菌丝生长和破坏细胞壁。此外，转录组学分析和代谢组学分析表明，能量代谢和氨基酸代谢途径的改变促进了虫草素的积累。最后，两个组学的整合分析证实鱼藤酮改变了核苷酸代谢途径向腺苷和上调虫草素合成基因 ( cns1-3 ) 将腺苷转化为虫草素。该工作首次报道鱼藤酮可以作为虫草素合成的有效诱导剂。