Redox-Active Coumarin Derivatives: Chemico-Biological Mechanisms Linking Oxidative Stress, Mitochondrial Dysfunction and Regulated Cell Death

Coumarin derivatives are structurally diverse benzopyrone-based compounds with broad relevance to medicinal chemistry, redox biology, mitochondrial pharmacology and photobiology. Their biological effects are highly context-dependent and are shaped by substitution pattern, concentration, metabolic activation, intracellular localization, metal coordination and light exposure. This review critically examines the chemico-biological mechanisms through which coumarin derivatives influence oxidative stress signaling, mitochondrial function and regulated cell death. Particular emphasis is placed on the distinction between chemical radical-scavenging activity observed in simplified assays and biologically relevant redox modulation in cells. Although hydroxy- and methoxycoumarins may display antioxidant capacity in chemical systems, their cellular effects are more plausibly mediated through redox-sensitive signaling pathways, including NRF2/KEAP1/ARE, NF-κB and MAPK, and through modulation of enzymatic antioxidant defenses rather than direct stoichiometric scavenging of oxidants in vivo. Conversely, selected synthetic hybrids, metal complexes, mitochondria-targeted derivatives and photoactivatable coumarins may promote ROS/RNS accumulation, nitric oxide-related signaling, calcium dysregulation, mitochondrial membrane depolarization, cytochrome c release, apoptosis, ferroptosis-associated lipid peroxidation, autophagy-associated responses and photodynamic cytotoxicity. We also discuss how tumor-cell heterogeneity, basal redox state, NRF2 activity, NF-κB dependence, metabolic context and antioxidant reserve may determine whether coumarin exposure results in cytoprotection, growth inhibition or cell death. Finally, we evaluate major translational and toxicological barriers, including metabolic liability, hepatotoxicity, phototoxicity, photogenotoxicity, limited in vivo validation, insufficient target-engagement data and mechanistic overinterpretation of ROS-related endpoints. A more critical chemico-biological framework is required to guide the rational development of coumarin-based therapeutic, phototherapeutic and theranostic candidates.