Augusta University
Stacey Hudson
Iron and copper help keep our cells alive. But under the wrong conditions, those same metals can help kill cells.
That paradox is at the center of a new review co-authored by Franklin R. Tay, BDSc, PhD, chair of the Department of Endodontics at the Dental College of Georgia and Yuan-Yuan Li from the National Clinical Research Center for Oral Diseases in Shaanxi, China. The study examines two forms of metal-dependent regulated cell death and their relevance to diseases ranging from cancer to oral conditions.
Published in Signal Transduction and Targeted Therapy, the review, “Cuproptosis and ferroptosis: signal pathways, diseases and therapeutic targets,” explores how cells respond when copper and iron disrupt normal functions, how these processes may contribute to disease and whether scientists could eventually turn them into targeted treatments.
The basic idea is simple: iron and copper are essential to normal cell function, yet disturbed metal handling can trigger cell death. Researchers are investigating whether these pathways can be activated in harmful cells or suppressed to protect vulnerable tissues.
“Cells have intricate systems that keep them functioning, and metals such as copper and iron are essential components of those systems,” said Franklin R. Tay, BDSc, PhD, co-author and chair of endodontics at Augusta University. “When those systems become disrupted, the consequences can extend to tissue health and disease.”
Think of a cell as a tiny city. Mitochondria are the power plants, producing energy to keep everything running. Its cell membrane is the protective wall. Copper and iron are among the resources the cell must carefully manage.
Cuproptosis occurs when excess copper interferes with proteins involved in mitochondrial metabolism. The copper can cause certain proteins to clump together and disrupt the cell’s energy-producing machinery. In the city analogy, copper gums up the power plant.
Ferroptosis takes a different route. Iron can promote chemical reactions that damage fatty components of cell membranes, a process called lipid peroxidation. As oxidative damage accumulates, membrane integrity fails, like deterioration of the city’s protective walls.
The distinction matters because this is not simply a case of having “too much metal.” Cells carefully use and dispose of copper and iron, and removing too much can also be harmful. The challenge is distinguishing harmful, chemically reactive or misplaced metals from amounts cells need to function.
The mouth is a particularly interesting place to study these processes because oral tissues constantly encounter injury, inflammation and infection. The review examines evidence linking these pathways to pulpitis, apical periodontitis, periodontitis, radiation-related oral injury, cancer and systemic disease.
The potential cancer connection is especially important. Cancer cells frequently have altered metabolism and energy requirements compared with healthy cells. Those differences may make some tumors more vulnerable to therapies designed to trigger ferroptosis or cuproptosis. Scientists are investigating whether they can exploit a cancer cell’s altered metal-handling machinery while minimizing effects on healthy cells.
The goal is not simply to make cells die. It is to make the right cells die at the right time while protecting healthy tissue. Cancer cells may adapt by altering metal transport, strengthening antioxidant defenses or switching to other survival mechanisms. Understanding those escape routes could help researchers develop treatments that make it harder for diseased cells to evade therapy.
The review describes several approaches researchers are investigating, including drugs that alter metal availability, compounds that influence ferroptosis and cuproptosis pathways, and nanoparticle-based systems designed to deliver treatments to specific tissues.
Because copper and iron are essential to normal physiology, simply depleting them throughout the body would not be safe. Future approaches could instead concentrate treatment in diseased tissue using nanoparticles, antibodies, peptides or locally activated drugs.
Despite the promise, therapies specifically designed to manipulate cuproptosis or ferroptosis remain experimental. Clinical studies have produced mixed results, and these pathways are not established therapeutic targets in routine care.
Significant questions remain. Researchers need to determine which patients are most likely to benefit, identify reliable biomarkers, understand how these pathways interact with the immune system and develop ways to target diseased tissue without disturbing the body’s normal copper and iron balance.
The science also raises a caution for patients tempted to experiment on their own. Adding extra iron or copper to the diet will not reproduce the carefully controlled cellular processes being studied in laboratories. Likewise, iron- or copper-removing drugs can have unintended effects. Patients should not attempt to manipulate these pathways without medical supervision.
For now, the significance of ferroptosis and cuproptosis lies in what they could teach researchers about disease. The most exciting possibility is selective manipulation: activating these pathways to eliminate harmful cells or suppressing them to protect vulnerable tissue.
For researchers, that could open new avenues for understanding how cells respond to inflammation, infection, injury and cancer and potentially lead to more precise approaches to treatment.
“We are still learning how these pathways work and how they interact with the many other systems that keep cells healthy,” Tay said. “The challenge is to understand when these pathways are harmful, when they might be beneficial to target and how to intervene without disrupting the body’s overall metal balance.”
Read the full study: “Cuproptosis and ferroptosis: signal pathways, diseases and therapeutic targets”
