Cordycepin-Enriched Cordyceps militaris Extract ARA815 Induces Ferroptosis in Lung Cancer Cells In Vivo and In Vitro

Cordyceps militaris, a traditional medicinal fungus and a promising food supplement, has demonstrated anticancer potential, yet its underlying mechanisms and in vivo efficacy remain poorly defined. Previously, we developed an optimized extraction and preparation protocol to enrich the bioactive content of C. militaris, specifically adenosine and cordycepin. Here, using this optimized C. militaris extract (CME), we investigated its antitumor effects and underlying mechanisms in a murine lung cancer model. Components of CME were quantified using high-performance liquid chromatography. In vivo, CME significantly suppressed tumor growth in LLC1-bearing mice. Mechanistically, CME induced ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and redox imbalance. Tumors from CME-treated mice displayed elevated lipid ROS, increased iron accumulation, glutathione depletion, and downregulation of glutathione peroxidase 4. Apoptotic signaling was accompanied with ferroptosis, but neither pyroptosis nor necroptosis contributed to CME-induced lung cancer death. Pharmacological rescue experiments confirmed the specificity of ferroptosis as the dominant mode of cell death. Importantly, CME caused no systemic toxicity, and its approximate lethal dose was over 5000 mg/kg. Together, these findings suggest CME as a potent ferroptosis-inducing agent against lung cancer and establish C. militaris as a promising candidate for redox-targeted cancer therapy.