Let’s Iron this Out: Ferroptosis and Dry Eye
Lipid peroxidation is a process in which lipids (fatty acid molecules) in the cell membranes are broken down by reactive oxygen species (ROS). This process can be very damaging to the cell, leading to oxidative stress and damage to proteins & DNA, eventually causing cell death.
The primary cause of lipid peroxidation is an imbalance between the production of ROS and the antioxidant capacity of the cell. When there is too much free radical activity or too few antioxidants present like Glutathione, oxidation of lipids occurs. Polyunsaturated fatty acids (PUFA's) are very prone to this process, and their rapid peroxidation in the body may limit the clinical benefit in some dry eye patients who use Omega-3 supplements. The mechanistic connection is well-established in dry eye, so much so that currently in development is a new drug that blocks reactive aldehydes, which are produced by lipid peroxidation.
Ferroptosis is a recently discovered form of regulated cell death that is Iron-dependent and occurs when lipid peroxidation is rampant. Unlike apoptosis and necrosis, ferroptosis does not involve caspase activity or ATP depletion; instead you get an accumulation of oxidized lipids that leads to mitochondrial dysfunction and ROS overload.
Ferroptosis has been linked to numerous diseases such as neurodegeneration, cancer progression, retinal degeneration, kidney fibrosis, cardiovascular disease, and also dry eye. Researchers suggest that disruption of ferroptosis may be a novel target for treating inflammatory conditions such as rheumatoid arthritis.
The combination of too much iron in the cell and antioxidant deficiency can perpetuate this perfect storm of cell destruction, affecting tissues in the eye. This can occur because of a combination of genetics, diet, and environment (especially chronic infections and stress). This does not mean Iron is "bad" and everyone should be on a plant based diet. It certainly solidifies the role of glutathione support, in foods and supplementation like we do in the dry eye nutrition program, as an adjunct to other treatments.
Iron lab testing and genetic analysis may help, in addition to assessment of biomarkers before starting Omegas (or if Omegas have previously failed). Studies indicate tear hyperosmolarity, a marker often used in dry eye workups to diagnose and manage the condition, may be associated with ferroptosis. Dr. Ioussifova and I start our journey with a patient referred to us by recommending a lab test that screens for lipid peroxidation and glutathione, among other biomarkers.
Since EPA and DHA are such important clinical tools, identifying and getting lipid peroxidation under control with a comprehensive regimen of dietary changes and fat soluble antioxidants could be a crucial first step in dry eye management.
For education and informational purposes only
References
1. Scarpellini C, Ramos Llorca A, Lanthier C, Klejborowska G, Augustyns K. The Potential Role of Regulated Cell Death in Dry Eye Diseases and Ocular Surface Dysfunction. Int J Mol Sci. 2023 Jan 1;24(1):731. doi: 10.3390/ijms24010731. PMID: 36614174; PMCID: PMC9820812.
2. Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med. 2013 Mar;56:89-101. doi: 10.1016/j.freeradbiomed.2012.11.010. Epub 2012 Nov 27. PMID: 23195683; PMCID: PMC3631350.
