Reactive oxygen species in cell signaling and cell death: A redox perspective on metabolic and inflammatory disorders

Reactive oxygen species (ROS) are chemically reactive oxygen derived molecules generated as unavoidable byproducts of metabolism and tightly regulated enzymatic reactions. Under physiological conditions, moderate ROS levels generate oxidative eustress that supports essential signaling functions, enabling cellular communication, metabolic regulation, immune defense, and adaptive stress responses. Beyond the cell-autonomous level, ROS function as critical systemic messengers that facilitate organ-organ communication, coordinating integrated physiological responses across distal tissues to maintain organismal homeostasis. Disruption of the balance between ROS production and antioxidant buffering capacity leads to redox imbalance or oxidative distress, resulting in oxidative modification of lipids, proteins, nucleic acids, and organelles and driving pathological outcomes. Importantly, ROS do not act solely as damaging agents but actively modulate major signaling pathways including NF-κB, MAPKs, PI3K/AKT, NRF2, HIF-1α, and Wnt/β-catenin, thereby shaping inflammation, metabolism, survival, and cell fate decisions. When redox control is lost, excessive ROS engage multiple regulated oxidative cell death programs such as apoptosis, ferroptosis, necroptosis, pyroptosis, paraptosis, parthanatos, oxeiptosis, and NETosis, each governed by distinct redox sensitive mechanisms. This failure of redox coordination underlies a broad spectrum of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, and diabetes. Collectively, these insights position redox organization, rather than bulk oxidative stress, as the critical determinant of signaling integrity, cell fate, and disease vulnerability, and as a key focus for future therapeutic innovation.