AhR restricts axon regeneration by balancing neuronal stress and growth response after injury

Abstract

Neurons must balance stress responses with regenerative demands following injury, but the mechanism is unclear. Here, we identify the aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, as a key regulator of this stress-growth switch. We show that ligand mediated AhR signaling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models. Mechanistic studies revealed that axotomy-induced AhR activation in dorsal root ganglion (DRG) neurons enforces proteostasis and stress-response programs to preserve tissue integrity. In contrast, AhR ablation redirects the neuronal response toward elevated de novo translation and pro-growth signaling, enabling axon regeneration. This growth-promoting effect required HIF-1, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response (ISR) and DNA hydroxymethylation to rewire neuronal injury programs. Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis, and metabolic signaling to control the balance between stress adaptation and axonal repair.