Reactive oxygen species act as dual regulators of organ regeneration

Reactive oxygen species, long dismissed as damaging byproducts of metabolism, are increasingly recognized as essential signaling molecules that help orchestrate organ regeneration, according to a review published in Cell Death Discovery. The article, authored by Yang Liu, Yi Zhu, Hao Cai, Tong Xu, Zhihang Zuo, Yujia Teng, Heng Wang, Xuebing Yan and Binxu Yin, synthesizes current knowledge on how redox chemistry shapes tissue repair across a wide range of species, from highly regenerative organisms to mammals whose healing tends to end in scarring.

The review frames this dual identity of ROS within an evolutionary context. The transition from anaerobic to aerobic life imposed significant oxidative challenges on living systems, but it also enabled the emergence of reactive oxygen species as regulators of cellular signaling. Molecules that once threatened cells with oxidative damage were gradually co-opted into communication networks that now influence how tissues respond to injury. The authors argue that this history helps explain why regeneration outcomes differ so dramatically between species.

Central to the review is the biphasic nature of ROS. At physiological levels, reactive oxygen species act as promoters of regeneration, participating in the signaling cascades that guide cells through repair programs. At pathological concentrations, however, the same molecules become inhibitors of regeneration, overwhelming cellular systems and pushing tissue toward damage rather than reconstruction. This dose-dependent switch means that regenerative success depends not simply on the presence or absence of ROS, but on where, when and at what level they appear.

Comparative analyses highlighted in the review suggest that species with high regenerative capacity share a common feature: precise spatiotemporal control of ROS dynamics. In these organisms, redox signals appear to be deployed with tight spatial and temporal precision, allowing the beneficial signaling functions of ROS to operate without tipping into harmful territory. The authors link this control to flexible redox homeostasis and to telomerase activity, both of which appear more permissive in regenerative species.

Mammals present a contrasting picture. The review notes that mammals exhibit stricter antioxidant regulation and telomerase restriction, features that the authors propose may underlie their limited regenerative potential and their propensity for fibrotic repair. In other words, the mammalian strategy of aggressively suppressing ROS, while protective against oxidative damage, may also blunt the regenerative signals that ROS can provide, leaving scar formation as the default outcome of significant injury.

The review also examines the interplay between oxygen-sensing pathways, antioxidant systems and ROS-mediated signaling networks in modulating regenerative outcomes. Because reactive oxygen species are intimately tied to oxygen metabolism, the pathways that sense oxygen availability and the enzymatic systems that neutralize oxidants jointly determine the redox environment a regenerating tissue experiences. The authors present this three-way interaction as a key determinant of whether injury resolves through regeneration or fibrosis.

By drawing these threads together, the authors aim to establish evolutionary and mechanistic principles that could inform new therapeutic thinking. They suggest that understanding how different species manage ROS signaling may offer novel insights for developing redox-based strategies to enhance tissue repair in humans. Such strategies would presumably seek to recreate the permissive redox conditions seen in regenerative species while avoiding the pathological oxidative states that block healing.

As a review article, the work does not report new experimental data; rather, it consolidates findings from studies across phylogenetically diverse species into a unified framework. Its central message is that regeneration is not simply a matter of which genes an organism possesses, but of how redox signaling is governed. The biphasic behavior of ROS, the precision of their spatiotemporal dynamics and the evolutionary divergence in antioxidant and telomerase regulation together form a picture in which the fate of injured tissue is written, in part, in its oxidation-reduction chemistry.

Subject of Research: The role of reactive oxygen species as signaling molecules in organ regeneration across species

Article Title: Redox Orchestration of organ regeneration

Article References: Liu, Y., Zhu, Y., Cai, H., Xu, T., Zuo, Z., Teng, Y., Wang, H., Yan, X., & Yin, B. (2026). Redox Orchestration of organ regeneration. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03294-6

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03294-6

Keywords: reactive oxygen species, organ regeneration, redox signaling, tissue repair, fibrosis, telomerase, antioxidants, oxygen sensing, evolutionary biology, Cell Death Discovery, Redox, Orchestration