Abstract The traditional view of reactive oxygen species (ROS) as uniform toxicants has been superseded by the recognition of a fundamental radical/non-radical dichotomy. As radical and non-radical ROS differ in spatial and kinetic behaviors that dictate cellular impacts, understanding this dichotomy is essential for the design of ROS-targeting therapies. However, the roles of specific ROS types under physiological and pathological conditions remain inadequately defined, hindering precise clinical translation. By organizing ROS sources, neutralizing systems, reaction kinetics, biological effects, and therapeutic strategies along a radical versus non-radical axis, this review clarifies their unique and shared attributes to facilitate effective exploitation for health and disease management. Radical species, being short-lived and membrane-confined, operate locally at near-diffusion-limited rates, whereas non-radical species support compartment-transcending redox communication. Both types mediate beneficial eustress at low physiological levels, suitable for health promotion; yet provoke oxidative distress at high concentrations, forming the basis for numerous therapeutic applications. We examine how this radical versus non-radical dichotomy guides contemporary redox interventions. In health, while low-dose radicals enhance stress resilience and metabolic adaptation, non-radicals regulate physiological plasticity; in disease, radical-focused therapies enable precise cytotoxicity, and non-radical approaches permit spatially programmable signaling. Furthermore, we highlight the promise of hybrid ROS-targeting strategies leveraging their capacity for synchronized and tunable delivery of both radical and non-radical species, enabling broad therapeutic potential. By delineating ROS biology along chemical and spatial principles, this framework advances targeted redox interventions for complex diseases, underscoring the indispensable role of radical processes in oncology.
Ren et al. (Fri,) studied this question.