Beyond Antioxidants: How ROS-RNS-RSS Microdomains Encode Redox Information in Health and Disease

Cellular redox biology is governed less by bulk oxidant load than by coupled ROS, RNS, and RSS behaviour within spatially restricted microdomains. Within these niches, redox information is written, edited, and erased through competing post-translational modifications, including sulphenylation (-SOH), S-nitrosation (-SNO), and persulphidation (-SSH). Local proximity to sources such as mitochondria, NOX, and NOS combines with buffering by SOD and peroxidases to shape which routes dominate. Editing by thioredoxin, glutaredoxin, and GSNOR, together with sulphane sulphur flux from trans-sulphuration enzymes and mitochondrial sulphide oxidation, sets the boundary between reversible redox eustress and pathological distress dominated by peroxynitrite chemistry and irreversible oxidation. Using a compartment-aware analytical template across cardiometabolic disease, neurodegeneration, cancer, chronic inflammation, ageing, and innate immunity, we identify recurring mechanistic patterns and explain why global biomarkers can mislead. We then propose context-matched biomarker panels and therapeutic levers, with antimicrobial peptides emerging as redox-modulated effectors of innate defence within this framework. Finally, we outline precision redox pharmacology that raises local distress thresholds without flattening physiological signalling, and we propose a trial-ready agenda centred on compartment-resolved pharmacodynamic anchors. • Redox signalling is governed by spatially restricted ROS, RNS and RSS microdomains, where kinetic competition among –SOH, –SNO and –SSH modifications determines biological outcome. • Transition from reversible eustress to pathological distress reflects collapse of local editing capacity and increased peroxynitrite chemistry rather than bulk oxidant burden. • Compartment-aware framework explains recurrent redox failure modes across cardiometabolic disease, neurodegeneration, cancer, inflammation and ageing. • Precision redox pharmacology should raise local distress thresholds while preserving physiological signalling, using organelle-targeted strategies and compartment-resolved pharmacodynamic anchors.