Researchers at the Icahn School of Medicine at Mount Sinai have identified a molecular mechanism that appears to restrict the ability of injured neurons to regrow damaged axons. The findings, published in the journal Nature, suggest that blocking a protein known as the aryl hydrocarbon receptor (AHR) could promote nerve regeneration and improve recovery after damage to peripheral nerves or the spinal cord.
Axons are long extensions of nerve cells, or neurons, that transmit signals throughout both the central and peripheral nervous systems. These fibers are essential for communication between nerve cells. When axons are damaged or severed, recovery depends heavily on whether neurons can rebuild those connections.
Why Damaged Nerves Struggle To Regrow
In adult mammals, however, neurons have only a limited capacity to regenerate their axons. As a result, injuries involving nerves or the spinal cord can cause long-lasting or permanent problems with movement and sensation. Understanding what prevents stronger regrowth has been a major challenge for researchers.
The new research points to AHR as an important regulator of 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.”
Researchers found that active AHR signaling suppresses axon growth. When they removed AHR from neurons or used drugs to block its activity, damaged axonal fibers regenerated more successfully. In mouse models involving peripheral nerve damage and spinal cord injury, suppressing AHR also led to better recovery of movement and sensation.
A Tradeoff Between Survival and Repair
Additional experiments helped explain why AHR has this effect. Following an injury, the protein supports a protective response that helps neurons maintain protein quality control — a process known as proteostasis. This system helps injured neurons withstand cellular stress, but it also limits the production of new proteins required for rebuilding axons.
Without active AHR, neurons appear to change priorities. They increase the production of new proteins and turn on biological pathways associated with growth and axon regeneration. The researchers found that this response also relies on another factor called HIF-1α, which helps control 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.”
An Unexpected Role for a Toxin Sensor
AHR was first identified because of its ability to detect environmental toxins and pollutants, termed xenobiotics. The latest findings indicate that its role extends beyond environmental sensing. Inside neurons, AHR appears to connect responses to the surrounding environment with the cellular processes that determine whether damaged axons can regenerate.
The discovery could eventually have therapeutic implications. Several drugs designed to inhibit AHR are already undergoing clinical trials for other conditions. That raises the possibility that researchers could one day investigate similar drugs as treatments for injuries involving peripheral nerves or the spinal cord.
Moving Toward Potential Treatments
The work remains at an early stage, and additional research will be necessary before AHR targeting could be considered for patients. Future studies will test how well AHR inhibitors work across different forms of neural injury, identify appropriate treatment timing and dosage, and examine how suppressing the protein affects other cells involved in the injury response.
The Mount Sinai team also plans to investigate AHR-blocking drugs and gene-therapy approaches that reduce AHR activity specifically in neurons. Researchers hope to determine whether these strategies can further enhance axon regeneration and improve recovery following spinal cord injury, stroke, or other neurological diseases.
