Pharmacological Strategies for Cataract Management: From Molecular Targets to Clinical Translation

Abstract

Cataracts, characterized by the opacification of the eye lens, remain a leading cause of reversible blindness globally. Age and diabetes are key risk factors, and with the increasing aging and diabetic population, the global burden of cataracts is projected to rise significantly. Current treatment is predominantly surgical; however, pharmacological strategies could offer a non-invasive alternative with the potential to delay, prevent, or even reverse cataract progression. Recent research has enhanced our understanding of cataractogenesis, emphasizing oxidative stress as a key underlying mechanism, but also including other processes such as calcium dysregulation and altered lens homeostasis or specific events induced by hyperglycemia in diabetic cataracts. New therapeutic approaches have emerged considering the molecular mechanisms involved in cataracts, most of which focus on pharmacological agents with antioxidant properties. Additionally, small-molecule chaperones, aldose reductase inhibitors, and protein aggregation inhibitors have also demonstrated potential in stabilizing or restoring lens protein structure and transparency. While experimental results have shown encouraging results, further research is needed to optimize drug delivery systems to the lens, assess long-term safety, and confirm the clinical efficacy of these treatments. This article reviews current progress in pharmacological treatments for cataracts, outlining challenges and prospects for future integration into clinical practice.

Keywords: aldose reductase inhibitors; antioxidant; cataract; drug delivery; oxidative stress; pharmacology; protein aggregation inhibitors.

Figure 1

Lens structure: Image showing the normal position of the lens within the eye (left) and architecture of the lens indicating the anterior and posterior lens capsules, the epithelial layer, and the nuclear and cortical fibers (right).

Figure 2

Cataract types according to location in the lens. Schematic diagrams representing the main types of cataracts: nuclear, posterior subcapsular, and cortical.

Figure 3

Imbalance between antioxidant defenses and reactive oxygen species (ROS) leads to oxidative stress and cataract formation. Antioxidants, including both enzymatic and non-enzymatic (glutathione, GSH) components, counteract oxidative stress mediated by ROS. Excess ROS—originating from exogenous sources like UV light and endogenous sources such as the mitochondrial electron transport chain—disrupts this balance, triggering oxidative stress. This cascade results in protein modification/aggregation, DNA damage, lipid peroxidation, and various forms of cell death (apoptosis, pyroptosis, and ferroptosis), culminating in cataract formation.

Figure 4

Mechanistic overview of osmotic and oxidative stress in diabetic cataract formation. Osmotic stress is initiated by the activation of aldose reductase (AR), which reduces glucose to sorbitol and is subsequently metabolized by sorbitol dehydrogenase (SDH). Accumulation of sorbitol contributes to cellular osmotic imbalance. Concomitantly, oxidative stress is driven by the excessive generation of reactive oxygen species (ROS) and impaired glutathione reductase (GR) activity, leading to lens damage and cataract development.

Figure 5

Disruption of calcium homeostasis and its role in cataract formation. Under physiological conditions, calcium homeostasis is tightly regulated. However, elevated intracellular calcium levels lead to pathological outcomes. Increased calcium activates connexin hemichannels and calpains. Connexin hemichannel activation contributes to homeostasis disruption, while calpain activation leads to crystallin protein degradation. These processes collectively disrupt lens transparency and contribute to cataractogenesis.