In most countries, cardboard cigarette packages display imagery or text that warns smokers of the increased risks of heart attacks, cancer and pregnancy complications that accompany lighting up. Many of these risks are associated with the inhalation of tobacco smoke through the mouth. But what is less often spotlighted is the effect smoking can have on the surface of the eyes.

Tobacco smoking has been tied to age-related macular degeneration, glaucoma and cataracts—some of the leading causes of blindness and severe vision loss worldwide. But these afflictions occur in inner regions of the eye: the retina, optic nerve and lens, respectively. Now researchers have discovered how cigarette smoke and aerosols from heated tobacco devices—which bake tobacco leaves rather than burning them or vaporizing liquid tobacco products—also kill cells in the eye’s most exposed layer: the cornea.

“This is the outermost surface of the eye that is exposed to environmental factors like chemicals, light and infection,” says Wataru Otsu, a biomedical researcher from Gifu Pharmaceutical University in Japan. Tobacco smokers are twice as likely as non-smokers to suffer from dry eye syndrome, which manifests as a dehydrated red and itchy eye surface that can lead to impaired vision, infections or corneal ulcers. Understanding how cigarettes and heated tobacco devices, which burn or emit aerosols just centimeters away, affect the eye’s most exposed tissue could help researchers develop better protections against eye damage, Otsu says.

In 2006 a clinical survey showed degradation of the tear film that coats and protects the surface of the cornea in smokers. And experiments on rats have demonstrated that exposure to cigarette smoke damages the animals’ corneas and tear glands.

In the new study, published online in September in Scientific Reports, Otsu and his colleagues reported that the compounds in cigarette smoke cause iron buildup that kills cells in a critical outer layer of corneal tissue called the corneal epithelium. Moreover the researchers found that even without smoke specifically drifting into eyes, corneas can come to harm: this iron-driven cell death occurred even when cells were exposed to other types of tobacco products.

The researchers exposed lab-grown cultures of human corneal epithelium cells to cigarette smoke extract—a solution that contains most of the ingredients inhaled by cigarette smokers. This extract is created by bubbling cigarette smoke through a solution and is often used in preclinical studies as an analogy for the smoke itself. The researchers also tested whether heated tobacco devices, otherwise known as noncombusted cigarettes or heat-not-burn devices, affected corneal cells in a similar manner. These devices bake tobacco leaves, producing aerosols without burning. “Many people use these new heated tobacco devices as alternatives to cigarettes, but we don’t know much about how these new devices affect human health,” Otsu says. It turns out that tobacco smoking or heating can still damage cells in the outer eye even when the product used contains no tar or nicotine. Nonsmokers’ corneas might also be affected by secondhand smoke if consistently exposed, he notes. The researchers have not yet tested the effect of vaping on the cells.

Otsu and his colleagues found that after 24 hours of exposure, more cells died in cultures that were exposed to cigarette smoke extract and heated tobacco aerosols—including those that did not contain nicotine—compared with cells that were not exposed to smoke or tobacco. A closer look revealed evidence of damaged cell membranes, clumps of iron and an abundance of damaged ferritin: a protein complex that stores the iron needed for cellular process such as DNA synthesis and division. Taken together, these signs indicated that exposing corneal cells to the tobacco products had induced a form of programmed cell death driven by iron called ferroptosis.

The process starts when compounds in the tobacco products make contact with the corneal cells, which leads ferritin inside the cells to start breaking down and releasing stored iron, Otsu explains. Some of this iron bunches together and reacts with naturally occurring hydrogen peroxide to produce hydroxyl radicals—highly reactive molecules that can harm cells. Normally the cells’ repair systems can cope with these radicals, but when too many accumulate, they damage fats in cell membranes, triggering the cells to die.

Otsu and his colleagues found that when they added chemicals that bind iron and compounds known to block ferroptosis into their cultures, more cells survived exposure to the various tobacco products, further implicating ferroptosis as the killer. The findings suggest ferroptosis treatments could help smokers who suffer from corneal damage.

Because the study involved cell cultures rather than live human eyeballs, the researchers are not yet able to say how quickly smoking or heated tobacco products damage a person’s corneas or how effective ferroptosis inhibitors are for treating smoking-related corneal diseases. The next steps will involve conducting animal experiments and testing the impact of vaping products on corneal cells, Otsu says.

But the results are already impactful, says Dilek Altinörs, an ophthalmologist at Başkent University in Turkey, who was not involved in the study. If smoke exposure breaks down lipids in corneal epithelium cells, the tear film that coats the cornea may suffer similarly, she speculates. Lipids in this film keep the eye from drying out, and smokers are already known to be more susceptible to damaged tear films and dry eye syndrome. But researchers have not yet investigated ferroptosis as a possible culprit.

This study motivates investigation into the efficacy of using tear drops that contain ferroptosis-blocking compounds to help smokers find long-term relief and protection from dry eye disease, a persistently irritating—and sometimes dangerous—condition, Altinörs says. “Maybe we can put these substances in artificial tears. It opens a whole new road for dry eye disease,” she adds.