A newly identified molecular mechanism reveals how neurons weigh survival against repair after injury.
Scientists at the Icahn School of Medicine at Mount Sinai have identified a molecular switch in neurons that limits the regrowth of damaged axons. Their study, published in Nature, suggests that blocking a protein known as the aryl hydrocarbon receptor (AHR) could promote nerve regeneration and help restore function after injuries to peripheral nerves or
the spinal cord.
Axons are long fibers that transmit signals between nerve cells, or neurons, throughout the central and peripheral nervous systems. These structures are essential for communication within the body. When axons are damaged, recovery depends on the neuron’s ability to regrow them.
In adult mammals, this ability is very limited. As a result, injuries to nerves or the spinal cord often lead to lasting or permanent loss of movement or sensation. Researchers have spent years trying to understand why this repair process is so constrained.
A Molecular Brake on Regeneration
The study found that AHR plays a central role in controlling how neurons respond to injury.
“When neurons are injured, they must deal with stress while also trying to regrow their axons,” said Hongyan Zou, MD, PhD, Professor of Neurosurgery, and Neuroscience, at the Icahn School of Medicine at Mount Sinai and the study’s senior author. “We discovered that AHR functions like a brake that shifts neurons toward managing stress rather than
rebuilding damaged connections.”
Experiments showed that active AHR signaling slows axon regrowth. When researchers removed AHR or blocked it with drugs, damaged axons regenerated more effectively. In mouse models of peripheral nerve and spinal cord injury, inhibiting AHR also improved both movement and sensory recovery.
Balancing Survival and Growth
Further analysis revealed why this happens. After injury, AHR helps neurons maintain protein quality through a process called proteostasis. This response protects cells under stress but limits the production of new proteins needed for repair.
When AHR is turned off, neurons shift priorities. They increase protein production and activate pathways that support axon growth. The team also found that this regenerative response depends on another factor, HIF-1α, which controls genes involved in
metabolism and tissue repair.
“This discovery shows that neurons use AHR to balance survival and regeneration,” Dr. Zou explained. “By releasing this brake, we can push neurons into a state that favors repair.”
A Dual Role for an Environmental Sensor
AHR was first identified as a receptor that detects environmental toxins, known as xenobiotics. The new findings show it also has an important internal role, helping neurons integrate environmental signals with their ability to regenerate after injury.
This research is an early step toward potential therapies. Several drugs that block AHR are already in clinical trials for other conditions, raising the possibility that they could be tested for nerve and spinal cord injuries.
However, more work is needed before this approach can be used in patients. Future studies will explore how well
AHR inhibitors work across different types of neural damage, determine optimal timing and dosage, and examine their effects on other cells after injury.
The Mount Sinai team plans to test both AHR-blocking drugs and gene therapy approaches aimed at reducing AHR activity in neurons. The goal is to see whether these strategies can further enhance axon regrowth and improve recovery after spinal cord injury, stroke, and other neurological disorders.
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