Reactive Oxygen Species Emerge as Ancient Drivers of Animal Regeneration

For decades, reactive oxygen species were cast almost exclusively as molecular villains—unstable, corrosive byproducts of metabolism that chew through DNA, proteins and lipids, driving aging and disease. But a sweeping new review published in Cellular and Molecular Life Sciences argues that this reputation is only half the story. Written by Aurore Vullien, Jennifer John, Christine Rampon, Enrique Amaya, Eric Röttinger and Eve Gazave, the analysis synthesizes fifteen years of evidence showing that ROS, far from being mere metabolic noise, have been co-opted repeatedly during animal evolution as indispensable signaling molecules that orchestrate one of biology’s most astonishing feats: the regeneration of lost body parts. From jellyfish and starlet sea anemones to flatworms, fish, frogs and axolotls, a burst of oxidation at the wound site now appears to be one of the most conserved opening moves in the entire regenerative playbook.

The central paradox the authors confront is chemical. ROS—including superoxide, hydrogen peroxide and hydroxyl radicals—are inherently reactive, which is precisely why uncontrolled ROS production is toxic. Yet evolution has exploited this very reactivity. Hydrogen peroxide, in particular, is small, electrically neutral and membrane-permeable, allowing it to diffuse rapidly through tissue and act as a broadcast signal. At wound margins, ROS can oxidize the cysteine residues of target proteins, reversibly altering the activity of phosphatases, kinases and transcription factors. In this way, a transient oxidative pulse functions as a second-messenger system, converting the physical fact of injury into a coordinated genetic and cellular response. The review frames this as oxidative eustress—beneficial, regulated stress—as opposed to the destructive oxidative distress associated with pathology.

What makes the new synthesis compelling is its comparative breadth. The authors assemble evidence spanning the metazoan tree, from cnidarians such as Hydra and Nematostella, which can rebuild entire bodies from small fragments, to planarian flatworms, annelids, echinoderms, fish, amphibians and mammals. In nearly every regenerative model examined, pharmacological or genetic suppression of ROS production—most often by blocking the NADPH oxidase enzymes, or NOXes, that generate superoxide at the wound—impairs regeneration. Conversely, exogenous hydrogen peroxide can, in some systems, partially rescue defective regenerative responses. The consistency of this pattern across such distantly related animals raises the tantalizing possibility that ROS signaling is not a collection of independent evolutionary accidents but a deeply rooted, possibly ancestral, component of the regeneration program.

The review is careful, however, to emphasize that conserved does not mean uniform. The regulatory roles and modes of action of ROS vary considerably among species, tissues and regenerative contexts. In some animals, ROS act primarily in the earliest wound-healing phase, recruiting immune cells and initiating proliferation; in others, oxidative signals persist into blastema formation, the mass of progenitor cells from which the new structure grows. The downstream targets differ as well: ROS have been implicated in activating Wnt, FGF, ERK and JNK signaling pathways, in modulating apoptosis, and in shaping the extracellular matrix, but the specific wiring differs from one organism to the next. This variability, the authors argue, is precisely why continued comparative study is essential. Only by mapping ROS involvement across many species can researchers distinguish genuinely common mechanisms from species-specific embellishments.

This comparative logic carries the review into deeper evolutionary waters. The evolutionary history of regeneration remains one of the great unresolved puzzles in biology. Why can a salamander regrow an entire limb while a mouse cannot? Why do some annelids regenerate their whole posterior body axis while closely related species fail at the same task? Two competing frameworks dominate the field: regeneration as an ancestral capacity repeatedly lost in lineages that traded it for other advantages, or regeneration as a trait independently gained, assembled from pre-existing wound-healing and developmental machinery. The authors argue that ROS data can inform this debate. If ROS signaling sits at the base of regenerative responses across the animal tree, it may represent an ancient, conserved layer of the process—one that lineages with poor regenerative abilities have not necessarily lost, but perhaps fail to deploy correctly.

That reframing has direct therapeutic implications, and it is here that the review makes its most forward-looking argument. Humans regenerate well in the liver, moderately in skin and bone, and hardly at all in the heart, spinal cord and limbs. If ROS signaling is a conserved trigger of regenerative programs, then modulating redox state could offer a lever to reactivate latent regenerative capacity in poorly regenerating human tissues. The concept is not fanciful. Studies in zebrafish and axolotl have shown that adjusting ROS levels can influence heart regeneration and appendage regrowth, and redox-sensitive pathways such as ERK and Wnt are already major targets of regenerative medicine research. The review suggests that a rigorous understanding of when, where and at what concentration ROS act could enable precisely timed redox interventions—boosting regeneration without tipping tissues into the oxidative damage that fuels fibrosis, inflammation and cancer.

The authors are equally candid about the obstacles. ROS are fleeting, highly reactive and difficult to measure with spatial and temporal precision, and many of the tools used to manipulate them—broad-spectrum antioxidants, generic NOX inhibitors—are blunt instruments with off-target effects. To address this, the review includes a supplementary compendium of the functional tools available to modulate ROS production in regeneration studies, cataloguing the main pharmacological inhibitors and activators as well as the principal targets for RNA interference, morpholino and knockout approaches. Standardizing and refining this toolkit, the authors contend, is a prerequisite for the field’s maturation. Without it, discrepancies between studies may reflect technical artifacts rather than genuine biological differences, muddying the comparative analyses on which evolutionary conclusions depend.

The review also identifies major knowledge gaps that will shape the next decade of work. The precise molecular targets of ROS during regeneration remain incompletely defined in most models; the dose, duration and gradients of oxidative signals at wounds are poorly quantified; and the interplay between ROS and other injury-induced signals—calcium fluxes, bioelectric gradients, mechanical forces and immune-derived cytokines—is only beginning to be explored. Another open question is whether ROS participate in the establishment of positional memory, the information that tells a regenerating blastema whether to build a hand, a tail or a head. Answering these questions will require combining live redox biosensors, genetic models and comparative approaches across species that span the breadth of regenerative ability, from master regenerators to refractory ones.

What emerges from the synthesis is a view of regeneration as a redox-gated process whose ancient logic may still be latent within our own cells. The authors, based at institutions including Université Paris Cité, Université Côte d’Azur, the University of Manchester, Sorbonne Université and École Normale Supérieure, argue that studying ROS across metazoan diversity serves a dual purpose: it illuminates how regeneration evolved, and it reveals why some species, including our own, regenerate poorly. Both lines of inquiry converge on the same practical prize—new strategies in regenerative medicine grounded in evolutionary insight rather than trial and error. If the oxidizing burst that follows injury truly is a conserved call to rebuild, then learning to read, and perhaps to amplify, that ancient signal could one day help human tissues do what salamanders have done for millions of years: grow back.

Subject of Research: The role of reactive oxygen species signaling in animal regeneration and its evolutionary and therapeutic implications

Article Title: Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches

Article References: Vullien, A., John, J., Rampon, C., Amaya, E., Röttinger, E., & Gazave, E. (2026). Understanding ROS signaling and evolution during animal regeneration offers promising opportunities for novel therapeutic approaches. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06392-x

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06392-x

Keywords: reactive oxygen species, ROS signaling, regeneration, regenerative medicine, oxidative eustress, NADPH oxidase, evolutionary developmental biology, blastema, wound healing, redox biology, hydrogen peroxide, comparative biology