Hye-Jin Park
Cordyceps militaris (C. militaris) is a medicinal fungus renowned for its diverse therapeutic properties, largely attributed to bioactive compounds such as cordycepin, polysaccharides, adenosine, D-mannitol, carotenoids, and ergosterol. However, the production and composition of these metabolites are highly influenced by cultivation conditions, highlighting the need for systematic optimization strategies. This review synthesizes current findings on how nutritional factors—including carbon and nitrogen sources, their ratios, and trace elements—and environmental parameters such as oxygen availability, pH, temperature, and light regulate C. militaris metabolite biosynthesis. The impacts of solid-state fermentation (using grains, insects, and agro-industrial residues) and liquid state fermentation (submerged and surface cultures) are compared, with attention to their roles in mycelial growth, fruiting body formation, and secondary metabolite production. Special emphasis is placed on mixed grain–insect substrates and light regulation, which have emerged as promising methods to enhance cordycepin accumulation. Beyond summarizing advances, this review also identifies key knowledge gaps that must be addressed: (i) the incomplete understanding of metabolite regulatory networks, (ii) the absence of standardized cultivation protocols, and (iii) unresolved challenges in scale-up, including oxygen transfer, foam control, and downstream processing. We propose that future research should integrate multi-omics approaches with bioprocess engineering to overcome these limitations. Collectively, this review highlights both current progress and remaining challenges, providing a roadmap for advancing the sustainable, scalable, and application-driven production of bioactive compounds from C. militaris.