Tissue damage signals dynamically modulate apical epithelial autophagy to gate regeneration onset

Persistent tissue damage remodels regenerative homeostasis, wherein sustained perturbation culminates in regeneration failure. Although autophagy is a key modulator of morphogenetic homeostasis, it remains unclear whether and how autophagy within regenerative organizers participates in damage dynamics. Here we show that an acute amputation pulse activates, whereas prolonged inflammatory signaling suppresses, autophagy predominantly in the apical epithelial cap (AEC) of the regenerating limb. Systemic delivery of chemically distinct pro-regenerative small molecules similarly reinstates AEC autophagy, suggesting that AEC autophagy constitutes a convergent therapeutic target for regeneration. Genetic ablation of AEC autophagy renders the appendage refractory to regrowth, whereas transient enhancement of AEC autophagy elicits rapid blastema formation. AEC autophagy governs epithelial bioelectric tone, intercellular signaling and pattern memory through on-demand degradation of FGF receptors. Collectively, these data establish a causal role for AEC autophagy in preserving regenerative homeostasis following injury. Impairment of AEC autophagy under chronic inflammatory load underlies regenerative failure, and its restoration by autophagy activators offers a new strategy for inducing limb regeneration in non-permissive contexts.