Coumarins as modulators of ferroptosis across cancer, neurodegeneration, and cardiovascular disorders

Background Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and oxidative stress. It has emerged as a key contributor to the pathophysiology of cancer, neurodegenerative disorders, and cardiovascular diseases. Coumarins, a diverse class of benzopyrone-derived compounds, exhibit antioxidant, pro-oxidant, and iron-chelating properties, suggesting their potential role in modulating ferroptotic pathways. Aim This review aims to systematically evaluate the role of certain coumarins as modulators of ferroptosis and to explore their therapeutic implications across major disease contexts. Methods A comprehensive literature analysis was conducted focusing on experimental and preclinical studies investigating the interaction between coumarins and ferroptosis-related mechanisms, including iron metabolism, lipid peroxidation, and antioxidant defense systems such as the GPX4/GSH axis. Results Available preclinical evidence indicates that coumarins exert dual regulatory effects on ferroptosis. In in vitro and limited in vivo cancer models, several derivatives promote ferroptotic cell death through GPX4 inhibition, increased lipid peroxidation, and disruption of system Xc − activity. Conversely, in preclinical neuronal and cardiovascular systems, coumarins exhibit protective effects in vitro and in vivo by enhancing antioxidant defenses, activating Nrf2 signaling, and maintaining redox balance. These context-dependent actions are closely linked to structural diversity and pharmacokinetic properties of the compounds. Conclusion Coumarins represent promising, yet underexplored, modulators of ferroptosis. However, clinical translation is currently restricted by major barriers, including low bioavailability and other pharmacokinetic challenges, a complete lack of direct clinical evidence, and the absence of standardized ferroptosis assessment methods. Addressing these limitations through robust in vivo validation is essential to clarify their therapeutic applicability.