Cordyceps, a traditional and precious Chinese medicinal herb, has attracted much attention for its core active ingredient, cordycepin, due to its unique biological activity. However, the rapid metabolism of cordycepin in vivo significantly limits its efficacy. The mechanism of this phenomenon can be systematically analyzed from six aspects: metabolic pathways, key enzyme action, chemical structural characteristics, temperature effects, gene expression regulation, and metabolite interactions.
Cordycepin metabolism in vivo mainly follows the purine nucleotide metabolic pathway. After entering the human body, it enters cells via nucleoside transporters and is rapidly deaminated under the catalysis of adenosine deaminase (ADA), converting into a biologically inactive metabolite—3'-deoxyhypoxanthine nucleoside. This process is the core of cordycepin metabolism and the main reason for its loss of activity. Although some cordycepin can be phosphorylated to cordycepin triphosphate, this proportion is extremely low, making it difficult to form an effective concentration, further weakening its bioavailability.
Adenosine deaminase (ADA) plays a "key catalyst" role in cordycepin metabolism. This enzyme is widely distributed in human tissues, with particularly high activity in the liver and kidneys, and can efficiently recognize and catalyze the deamination reaction of cordycepin. Studies have shown that the activity level of ADA directly affects the metabolic rate of cordycepin: in individuals with high ADA expression or enhanced activity, the half-life of cordycepin may be shortened to the minute level, making it difficult to maintain an effective concentration in vivo. This characteristic poses a challenge to cordycepin when used alone, resulting in short-lived efficacy and the need for frequent dosing.
The chemical structure of cordycepin also determines its metabolic fate. As a structural analog of adenosine, cordycepin is composed of adenosine and deoxypentose, a structure that makes it easily recognized and catalyzed by ADA. In contrast, other nucleosides (such as pentostatin) have greater metabolic stability due to structural differences. Furthermore, the phosphorylation process of cordycepin depends on the participation of phosphorylase (ADK), but this process is inefficient, further limiting the formation of its active metabolites.
Temperature, as a core environmental factor affecting fungal metabolism, plays a dual role in the synthesis and degradation of cordycepin. Studies have shown that *Cordyceps* mycelium grows optimally at 22°C, but cordycepin production peaks at 25°C. High temperatures (>25°C) significantly reduce enzyme activity and accelerate antioxidant damage, leading to decreased cordycepin synthesis. In the human body, body temperature (37°C) may accelerate cordycepin metabolism, further shortening its half-life. This temperature sensitivity suggests that the metabolic rate of cordycepin may fluctuate due to individual differences in body temperature or changes in environmental temperature.
Gene expression regulation is a deep-seated mechanism of cordycepin metabolism. Transcriptomic studies have found that temperature stress induces reprogramming of *Cordyceps* gene expression, affecting pathways such as ribosome biosynthesis, amino acid metabolism, and energy metabolism. For example, high-temperature stress can upregulate the expression of genes related to cell membrane components while downregulating genes related to protein synthesis; this change may indirectly affect the synthesis and metabolism of cordycepin. Furthermore, the regulatory role of key transcription factors (such as SPAC1002.12c and fap1/fap2) may further regulate the metabolic rate of cordycepin by affecting the expression levels of metabolic enzymes.
The interactions between cordycepin and other metabolites are also significant. For example, pentostatin, found in Cordyceps militaris, can act as a "protective shield" for cordycepin, extending its degradation cycle by inhibiting ADA activity. However, this synergistic effect has not been fully validated in cordyceps. In addition, the coexistence of cordycepin with polysaccharides, adenosine monophosphate, and other components may indirectly affect its metabolic rate through competitive metabolic pathways or enzyme activity regulation. This complexity challenges the efficacy evaluation of single components, requiring a comprehensive analysis from the perspective of the overall metabolic network.
The rapid metabolism of cordycepin in vivo is the result of the combined effects of metabolic pathways, enzyme catalysis, chemical structure, temperature response, gene regulation, and metabolite interactions. This characteristic not only limits its clinical application but also suggests the need to improve its metabolic stability and bioavailability through structural modification, combination therapy, or optimized extraction processes. Future research needs to further elucidate the metabolic synergistic mechanisms of other components in cordyceps, providing a theoretical basis for the development of efficient and stable cordycepin derivatives.
