Abstract Hydrogen peroxide (H 2 O 2 ) is a crucial signaling molecule in vertebrate regeneration, yet its functional role across diverse lizard species remains incompletely defined. This study elucidates the master regulatory function of H 2 O 2 during tail regeneration in the lizard Scincella tsinlingensis using integrated pharmacological, morphological, histological, and transcriptomic approaches. Pharmacological modulation revealed that H 2 O 2 markedly enhances regeneration, achieving 5.89 ± 0.69 mm tail length at 21 days post-amputation (dpa), whereas ROS inhibition severely impairs regenerative outgrowth (0.88 ± 0.07 mm). Transcriptomic analysis at 7 dpa demonstrated that H 2 O 2 establishes fundamentally distinct molecular trajectories, with only 5 common differentially expressed genes (DEGs) shared between the DMSO-vs-APO (713 DEGs) and DMSO-vs-H 2 O 2 (593 DEGs) comparisons. Functionally, H 2 O 2 synchronizes three core pathways—phagocytosis, immune regulation, and cellular motility—into an integrated repair program while temporally coordinating MAPK, mTOR, Wnt, and Hippo-YAP signaling cascades. This establishes a sequential regulatory framework where the immediate post-amputation period constitutes an H 2 O 2 -dependent critical window with limited plasticity, explaining the only partial rescue achieved with delayed intervention. Transcriptomic data further suggest inferred associations of NADPH oxidase 2/DUOXA2-derived H 2 O 2 with cellular proliferation, YAP1 expression, potential EMT (via HIF-1α), as well as G2/M arrest and chromatin remodeling. These findings support the paradigm that ROS act as evolutionarily conserved, spatiotemporal integrators of tissue repair, coordinating injury response, immune modulation, metabolic reprogramming, and developmental pathway activation. This work provides a mechanistic foundation for developing redox-based therapies aimed at enhancing regeneration in clinical contexts of impaired healing.
Zhang et al. (Tue,) studied this question.