Redox Orchestration of organ regeneration

Abstract The evolutionary transition from anaerobic to aerobic life imposed significant oxidative challenges, while also enabling the emergence of reactive oxygen species (ROS) as key regulators of cellular signaling. This review synthesizes current knowledge on how ROS, once considered merely toxic byproducts, have been co-opted as essential signaling molecules that orchestrate organ regeneration across phylogenetically diverse species. We highlight the biphasic nature of ROS—acting as promoters of regeneration at physiological levels but as inhibitors at pathological concentrations—and explore how this duality has been shaped by evolutionary pressures. Comparative analyses reveal that species with high regenerative capacity exhibit precise spatiotemporal control of ROS dynamics, often linked to flexible redox homeostasis and telomerase activity. In contrast, mammals exhibit stricter antioxidant regulation and telomerase restriction, which may underlie their limited regenerative potential and propensity for fibrotic repair. We further discuss the interplay between oxygen-sensing pathways, antioxidant systems, and ROS-mediated signaling networks in modulating regenerative outcomes. Understanding these evolutionary and mechanistic principles offers novel insights for developing redox-based therapeutic strategies to enhance tissue repair in humans.