Oxidative inhibition of PTEN links ROS signaling to regeneration and homeostasis

Reactive oxygen species (ROS) are early signals of tissue damage, but how they engage growth-promoting pathways in vivo is unclear. Here we show that ROS promote regeneration by inhibiting PTEN, thereby activating PI3K-Akt signaling in Drosophila melanogaster. We identify cysteine 79 as an essential residue for redox regulation of PTEN, demonstrating that a ROS-insensitive PTEN mutant uncouples Akt activation from oxidative stress. This disruption impairs regenerative growth in wing imaginal epithelia and stem cell proliferation in the adult gut. Mechanistically, Akt activation links ROS signaling to p38 MAPK-dependent regeneration responses. Together, our findings define a conserved ROS-PTEN-Akt signaling axis that integrates oxidative damage with regenerative growth, establishing PTEN as a key redox-sensitive regulator of tissue repair.