Pleiotropic Bioactivity of Caterpillar Fungus and Cordycepin: Insight from Integrated Network Pharmacology and Food and Drug Regulatory Framework

The medical mushroom Ophiocordyceps sinensis (Caterpillar Fungus) is one of the most popular medicines in Asian traditional medical systems for its pleiotropic indications, including an ability to enhance “vitality”. However, the polyvalent adaptogenic potential of O. sinensis has not been systematically proven, and a consolidated mechanistic synthesis integrating both network predictions and experimental validation is lacking. The primary aim of this narrative review was to provide a rationale for the pleiotropic therapeutic effects of two traditionally used botanicals from the Fungi Kingdom (O.sinensis and the related fungus Cordyceps militaris (Orange Cordyceps) and their primary metabolite, cordycepin, using a network pharmacology approach to support or refute their adaptogenic potential. The secondary aim was to identify the source of temporary failures in marketing authorization for TCM products in Europe, arising from an ambiguous fundamental approach to the action of the same natural product across Western and Oriental medical systems. and provide a possible, reasonable solution. This review, for the first time show that: • O. sinensis, C. militaris, and 3-deoxyadenosine share a common adaptogenic mechanism for maintaining cellular and integrated biological system functions homeostasis. • The systems-level adaptogenic mechanism of these fungi is characterized by their ability to modulate multiple interconnected biological networks rather than acting on a single target. • This is in line with holistic TCM and Ayurvedic concepts and the modern concept of the pleiotropic therapeutic activity of adaptogens, particularly of O. sinensis, including cordycepin. • Their polyvalent pharmacological activity is related to the high content of nucleotides adenosine and cordycepin in these fungi, and to their involvement in metabolism and in signaling via protein kinases (PKB/Akt, PI3K, AMPK, and MAPK), which regulate diverse cellular processes and physiological functions • Network pharmacology studies identify multi-target pathways, including convergent hubs, such as PI3K-Akt, AMPK–mTOR, MAPK, apoptosis, and Nrf2. • By influencing pathways associated with immune regulation, mitochondrial function, and metabolic adaptation, they orchestrate a holistic response that enhances the organism's resilience to various stressors. • Validation studies confirm predictions across chronic obstructive pulmonary disease, pulmonary arterial hypertension, cancer, obesity, influenza, and immunogenicity. • This integrative effect is especially significant in the context of complex disorders, where multifactorial interventions are necessary for effective therapeutic outcomes. • The review reveals controversy regarding the bioavailability of cordycepin in vivo and its concentration in vitro studies, raising the hypothesis that cordycepin may act as a driver, triggering the organism's adaptive stress response in stress-induced and aging-related diseases. This review clarifies conceptual and regulatory barriers to recognizing resilience-supporting interventions and informs future regulatory innovation. The review for the first time suggests establishing a regulatory category for resilience-supporting physiological modulators that could align food and drug regulation in the EU with contemporary systems biology, thereby complementing EFSA, EMA, FDA, and Asian authorities. Overall, from a scientific point of view, both reductionistic and holistic integrative approaches are complementary and essential for understanding the mechanism of action of adaptogens and for the discovery of new effective therapeutics. Future research should focus on rigorous quality control and regulatory alignment to support evidence-based clinical use.