The Role of Artemisinin and its Derivatives in Cancer Therapy via Ferroptosis:A Systematic Review of In Vitro, In Vivo, and In Silico Studies

Introduction: Artemisinin (ART), a sesquiterpene lactone derived from Artemisia annua L., and its semisynthetic derivatives such as dihydroartemisinin (DHA) and artesunate (ARTE) have gained significant attention for their anticancer potential beyond their established antimalarial effects. The antitumor activity is mediated by various mechanisms, with ferroptosis—an iron-dependent, non-apoptotic form of cell death characterized by lipid peroxidation—standing out as a key pathway. Recent in vitro, in vivo, and in silico studies suggest that artemisinin compounds can trigger ferroptosis in various cancers, including breast, liver, pancreatic, and glioma, by disrupting iron homeostasis, inhibiting glutathione peroxidase 4 (GPX4), and increasing reactive oxygen species (ROS) accumulation. Methods: A comprehensive literature search was conducted up to 2025 using relevant keywords related to artemisinin, cancer, and ferroptosis in databases such as PubMed, Web of Science, and Scopus. Results: Experimental studies demonstrate that dihydroartemisinin and artesunate elevate intracellular Fe²⁺ levels and promote ROS-mediated lipid peroxidation. Animal models further validate these effects, showing tumor growth suppression with minimal systemic toxicity. In silico analyses support these findings, revealing interactions between artemisinin derivatives and ferroptosis-related proteins like GPX4 and transferrin receptor 1 (TfR1 Discussion: The findings collectively indicate that artemisinin and its derivatives induce ferroptosis through irondependent ROS accumulation and GPX4 inhibition, positioning ferroptosis as a central mechanism underlying their anticancer activity. Conclusion: This review analyzed 66 original research articles and identified ferroptosis as the primary mechanism by which artemisinin and its derivatives exert anticancer effects, often in combination with apoptosis, autophagy, or cell cycle arrest. In silico studies confirm strong interactions with ferroptosis-related targets. Lung and liver cancers emerged as the most frequently studied and responsive, highlighting them as key targets for future translational efforts. Standardized methodologies are needed to improve reproducibility and clinical relevance.