Broccoli to the Rescue?

Researchers from NYU Grossman School of Medicine and L V Prasad Eye Institute show through cell-based experiments that restoring NRF2 activity, a key regulator of the cell’s defence against oxidative stress, could be a possible therapeutic approach for keratoconus. 

Every cell in our body generates unstable molecules called reactive oxygen species (ROS) as a by-product of metabolism. When present in small levels they regulate several biological processes, but excessive levels can damage proteins, fats, and DNA that can cause cell death.

To prevent this, as part of the body’s internal defence system, cells rely on antioxidants–molecules that neutralize ROS. When this protective system is disrupted, it creates an imbalance between ROS and antioxidants, and the cells enter a state known as oxidative stress. 

One of the proteins that regulates this antioxidant response is nuclear factor erythroid 2-related factor 2 (NRF2), often described as the cell’s master regulator of antioxidant defence. 

Under normal conditions, NRF2 remains inactive inside the cytoplasm of the cell. But under oxidative stress, it moves into the nucleus and switches on genes involved in antioxidant and detoxification pathways, helping cells repair damage.

Researchers hypothesize that this protective system does not function as it should in keratoconus (KC), a disease in which the cornea gradually thins and bulges outward, distorting vision. This change in shape occurs because the collagen framework that gives the cornea its strength weakens.

Previous studies have shown that genes involved in the NRF2 pathway are disrupted in corneas with KC. However, what molecular changes affect the cornea’s antioxidant system and its role in keratoconus pathogenesis? 

In a new study published in Investigative Ophthalmology & Visual Science, Madhuri A. Koduri, Shukti Chakravarti, and colleagues from NYU Grossman School of Medicine in collaboration with Rohini Sonar, Rashmi Deshmukh, and Vivek Singh from LVPEI explore NRF2 disruption by studying corneal cells and analyzing tear samples.

They experimented on stromal fibroblasts (cells that make up the thick middle layer of the cornea that produce and maintain the collagen framework) to examine how cells from people with and without keratoconus respond to oxidative stress. The researchers then tested whether restoring NRF2 activity with sulforaphane, a naturally occurring compound found in broccoli, could improve the cells’ antioxidant response.

They also blocked NRF2 activity in healthy donor cells to determine whether this alone could reproduce features of keratoconus. The team then analysed tear samples from 57 people with keratoconus, and 34 unaffected individuals, to determine whether markers of oxidative stress could also be detected in patients.

The study found that keratoconus stromal fibroblasts showed reduced NRF2 activity than healthy donor cells, suggesting they had less ability to withstand oxidative stress. Increasing NRF2 activity with sulforaphane lowered oxidative stress and improved cell survival, whereas blocking NRF2 in healthy cells reproduced several features of keratoconus, including reduced expression of antioxidant genes, reduced cell growth and decreased extracellular matrix deposition.

The researchers also found higher levels of two oxidative stress markers in tears from people with keratoconus. The findings imply that impaired antioxidant defences contribute to keratoconus, and so, the NRF2 pathway is a potential target for therapeutic treatment of keratoconus. 

‘Keratoconus is influenced by multiple risk factors, including frequent eye rubbing, allergic conditions, genetic predisposition, and consanguinity. As scientists, we recognize that understanding disease mechanisms is the first step toward developing transformative therapies. Although the clinical features of keratoconus are well established, its underlying pathology remains elusive. Our team, in collaboration with national and international partners, is building reliable large-animal models and exploring tear-based biomarkers to identify key immunological and biological differences between patients and healthy individuals. These efforts will help us gain deeper insights into disease progression and ultimately improve patient outcomes,’ said Vivek Singh, Lead Scientist at the Centre for Ocular Regeneration and Engineering (CORE), L V Prasad Eye Institute.

Citation

Koduri MA, Charter M, Sonar R, et al. Oxidative stress in keratoconus is evident in tear fluid and stromal cells and alleviated in cell culture by sulforaphane. Invest Ophthalmol Vis Sci. 2026;67(5):1. https://doi.org/10.1167/iovs.67.5.1

Photo credit: Broccoli; Lance Cheung; CC BY 2.0