Ferroptosis Plays a Potential Role in Dry Eye Pathogenesis

Corneal epithelial cells may undergo oxidative stress-mediated ferroptosis due to the abnormal expression of the aldo-keto reductase, family 1, member C1 gene (AKR1C1), according to research published in Investigative Ophthalmology & Visual Science. These findings may provide a potential gene target for dry eye disease (DED) therapy. 

Ferroptosis, defined as iron-dependent apoptosis, is correlated with acute kidney injury, neurologic disorders, and various tumors. This study is the first to show evidence of ferroptosis in DED.

Researchers used a FerroOrange fluorescent probe and various other modalities to examine 72 mouse models and determine the precise mode of apoptosis underlying DED. They examined marked changes in ferroptosis-related markers expression, intracellular iron accumulation, and lipid peroxidation in eyes with DED. Western blotting and immunofluorescence staining were used to measure protein expressions, and mRNA expression was evaluated via RNA-sequencing and quantitative reverse transcription polymerase chain reaction testing.

Compared with mice in a control group, the density of red fluorescence, which represents the intracellular Fe²⁺ content, was significantly higher in those with DED.

Using an immortalized human corneal epithelial cell line cultured under hyperosmolarity, the researchers also examined the effect of AKR1C1 gene inhibition in eyes with ferroptosis-mediated damage. They found that a reduction in AKR1C1 expression resulted in decreased cell viability and increased lipid peroxidation. The researchers reported opposite effects with the overexpression of AKR1C1. 

“Our RNA-seq[uence] analysis of corneal epithelial cells showed that the mRNA expression of ferroptotic factors has increased and that of antiferroptotic factors has decreased in DED,” the researchers report. “Furthermore, the increase in the intracellular iron content combined with the accumulation of lipid peroxides induced by excessive oxidative stress indicated that ferroptosis might occur in dry eye.”

These study results show that ferroptosis-induced oxidative stress may be a factor in the development of DED. The upregulation of the AKR1C1 gene may significantly protect against the occurrence of corneal epithelial cell damage.