Researchers Identify Molecular ‘Brake’ That Limits Nerve or Spinal Cord Regeneration

Researchers from the Icahn School of Medicine at Mount Sinai have discovered a molecular switch in neurons that limits the regrowth of damaged axonal fibers. Published in the journal Nature, the findings show that blocking a protein called the aryl hydrocarbon receptor (AHR) may help neural regeneration and restore function after injuries to the peripheral nerves or spinal cord.

Axons are long fibers that carry signals between nerve cells, or neurons, in both the central and peripheral nervous systems. Axons are essential for communication in the nervous system, and when they are cut or damaged, recovery depends on the neuron’s ability to regrow these fibers.

Neurons in adult mammals have a limited ability to regrow their axonal connections, so injuries to the nerves or spinal cord often lead to long-lasting or permanent movement or sensation loss. Scientists have long been trying to understand the reasons this repair process is so restricted.

In the new study, investigators found that AHR acts as a key regulator for determining the way neurons respond after injury.

“When neurons are injured, they must deal with stress while also trying to regrow their axons,” said study senior author Hongyan Zou, M.D., Ph.D., professor of Neurosurgery and Neuroscience at Mount Sinai’s Icahn School of Medicine. “We discovered that AHR functions like a brake that shifts neurons toward managing stress rather than rebuilding damaged connections.”

The research team showed that when AHR signaling is active, it slows down axon growth. But when the researchers removed AHR from neurons or blocked it with drugs, axonal fibers regrew more effectively. In mouse models of peripheral nerve injury and spinal cord injury, inhibiting AHR also improved recovery of motor and sensory function.

Further experiments revealed how this process works. After injury, AHR helps neurons protect themselves by maintaining protein quality control—a process known as proteostasis. While this protective response helps neurons cope with stress, it also reduces the production of new proteins needed for growth.

When AHR is turned off, neurons shift their strategy. They begin producing more new proteins and activate growth-related pathways that support axon regeneration. The researchers also found this growth response depends on another factor called HIF-1α, which helps regulate 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.”

AHR was originally identified as a sensor that detects environmental toxins and pollutants, termed xenobiotics. The new findings suggest that AHR also plays an unexpected role inside neurons by integrating environmental sensing and regenerative capability to regrow axons after injury.

The study is an early step toward possible treatments. Several drugs that block AHR are already being tested in clinical trials for other diseases, raising the possibility they could eventually be studied for nerve or spinal cord injuries.

More research is needed before this approach can be used in patients. Future studies will examine AHR inhibitors’ efficacy in different types of neural damage, determine the best timing and dosage for treatment, and assess the impact on other cells after injury.

The Mount Sinai research team plans to test AHR-blocking drugs and gene-therapy strategies designed to reduce AHR activity in neurons. The goal of this next research stage is to determine whether these approaches can further boost axon regrowth and improve recovery after spinal cord injury, stroke, or other neurological diseases.

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, over 600 research and clinical labs, a school of nursing, and a school of medicine and graduate education. Mount Sinai advances health by discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities through high-quality care.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers healthcare solutions from birth through geriatrics, leveraging approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report’s “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report “Best Hospitals” Honor Roll for 2025-2026.