Abstract

Summary Salamanders possess the extraordinary ability to regenerate limbs throughout life, whereas Xenopus lose this capacity after metamorphosis, producing only rudimentary "spikes" after limb amputation. Here, we investigate the underlying mechanisms governing these distinct regenerative outcomes by focusing on the role of endogenous oxygen consumption and reactive oxygen species (ROS) dynamics. The transcriptomic analysis indicated that Xenopus undergo intense oxidative metabolism and DNA damage during metamorphosis, which was conspicuously absent in salamanders. Experimental hyperoxic conditions significantly impede early blastema formation and disrupt patterning in salamanders, while hypoxia accelerates limb regeneration in Xenopus tadpole. Furthermore, scavenging ROS during the refractory period in Xenopus promotes limb regeneration and patterning. These findings identify intrinsic oxidative stress as a critical barrier to regeneration and suggest that reducing oxidative stress could enhance regenerative outcomes.