Cataracts are the most common cause of vision loss in people over the age of 40 and are the leading cause of blindness worldwide. According to the latest assessment from the World Health Organization, over half of the cases of blindness worldwide may be attributed to cataracts [1]. Patients with cataracts experience clouded, blurred, or dim vision. The impact of vision loss and the resultant decline in quality of life have been well-documented. The average cost of cataract surgery worldwide can be as high as $4,000 per procedure, which can be particularly burdensome for patients in underdeveloped countries [2]. Furthermore, surgery-related complications such as posterior capsular opacity, intraocular lens dislocation, eye inflammation, photopsia, ocular hypertension, and macular edema can be severe, potentially leading to irreversible blindness [3]. Therefore, there remains a pressing need to identify non-surgical therapeutic options with benefits outweighing the risks of surgery.

Ultraviolet (UV) radiation is a known contributor to cataract development, especially in regions with increased UV exposure, such as high-altitude areas [4]. The sun, as the most potent source of UV radiation in our environment, emits three types of UV radiation: UVA, UVB, and UVC. UVA (320-400 nm) and UVB (290-320 nm) radiation comprise the majority of solar UV that penetrates the atmosphere, while most of the higher energy UVC (100-290 nm) is absorbed by the Earth's ozone layer [5]. The intense energy of UV light triggers an overproduction of reactive oxygen species (ROS), causing damage to lens epithelial cells (LECs), disrupting energy metabolism pathways, leading to DNA damage, promoting insoluble protein aggregation, and ultimately resulting in lens opacity [6], [7], [8], [9]. Recent research by Lou's team has revealed that aged mice are more susceptible to UV-induced cataract formation, leading to severe lens opacity, significant metabolic changes, and substantial redox imbalance [10]. Conversely, young mice exhibit greater resistance to UV radiation and have the capacity to repair UV-induced damage, gradually restoring lens clarity over 10 days post-UV exposure. This study suggests that the robust antioxidant enzymes present in young lenses may act as an intrinsic defense system within the lens. To maintain transparency, a healthy lens effectively utilizes various antioxidants and oxidation defense enzymes to protect against oxidation. However, with aging, the repair enzymes gradually lose their functionality, and the biosynthesis and recycling system for small molecule antioxidants becomes less efficient, leading to protein oxidation, aggregation, and eventually lens opacification [11].

Besides oxidative damage, UV-induced apoptosis in LECs also plays a significant role in cataract formation. An increasing body of evidence suggests that apoptosis in LECs is an initiating event in non-congenital cataract formation [12], [13], [14], [15], [16]. UV stress triggers apoptosis in LECs through the modulation of the JNK pathway, promoting caspase-3 cleavage, and activating the DNA fragmentation factor [12,15,17]. Antiapoptotic agents, including epigallocatechin gallate [18] and caffeine [19,20] have demonstrated effectiveness in preventing UV-induced lens opacity. Thus, the identification of a safe compound that can maintain redox balance and protect LECs from UV-induced apoptosis seems a feasible approach towards discovering new treatments for cataracts. Including fruits or plants with antioxidant properties in one's diet could enhance defense against oxidative stress and may serve as a strategy for cataract prevention.

The medicinal value of the grapevine and its fruit, Vitis vinifera, has been recognized for over 6,000 years. Historically, grapes were employed for a diverse array of therapeutic applications, including alleviating symptoms of nausea, addressing constipation, managing cholera, countering smallpox, ameliorating liver ailments, and even targeting specific types of cancer [21], [22], [23]. Numerous recent studies have highlighted the health benefits of grapes. For example, grape consumption improves glucose tolerance and reduces markers of inflammation in obese mice [24]. Grape supplementation prevents anxiety-like behavior, memory impairment, and high blood pressure in rats [25], [26], [27]. Clinical studies have also shown that grape polyphenols lower blood pressure and increase flow-mediated vasodilation in men with metabolic syndrome [28]. A recent study has indicated that consuming grapes significantly reduces the incidence of UV-B-induced skin carcinogenesis [29].

Grapes are well-known for their rich content of bioactive compounds, which include various polyphenols such as resveratrol, flavans like catechin, flavonols including quercetin, anthocyanins, and simple phenolics [30]. Resveratrol, in particular, has gained substantial attention due to its pharmacological potential. It activates SIRT1, an enzyme critical in regulating aging, stress responses, and cellular metabolism. Resveratrol exhibits a wide range of pharmacological effects, including antioxidant properties, cardioprotection, liver protection, anti-cancer activities, antibacterial effects, anti-inflammatory actions, and anti-aging effects [31].

On the other hand, catechins directly scavenge ROS and chelate metal ions. They also demonstrate indirect antioxidant activities by boosting antioxidant enzymes, inhibiting pro-oxidant enzymes, and enhancing phase II detoxification enzymes. The consumption of foods rich in catechin has been linked to various health benefits, such as increased plasma antioxidant activity, vasodilation, and reduced risk of atherosclerosis [32]. Recent studies have also indicated that catechin may help to maintain a healthy and thriving population of beneficial gut bacteria [33].

Quercetin, a potent antioxidant flavonoid primarily found in grapes, berries, citrus fruits, broccoli, and onions, has been extensively studied for its wide range of health benefits. These include anti-inflammatory, antihypercholesterolemic, vasodilatory, and antiatherosclerotic activities, as well as potent anti-tumor properties through the induction of apoptosis and cell cycle arrest in brain, liver, and colon cancer cells [34,35]. Interestingly, some studies during the pandemic revealed that quercetin exhibits anti-Covid-19 activity by inhibiting the expression of the human ACE2 receptors, which the virus uses for cell entry [36]. Although quercetin supplementation could not prevent Covid-19 infection, a recent clinical trial indicated its positive effect on patient recovery and relevant laboratory results [37].

Anthocyanins, water-soluble phenolic pigments found in red, purple, and blue fruits and vegetables, including grapes, are renowned for their strong antioxidant and anti-inflammatory activity. They have been shown to have anti-aging, antidiabetic, anticancer properties, and play a role in cardiovascular health and neuroprotection [38]. Clinical studies have also demonstrated that dietary interventions with anthocyanins may decrease oxidized low-density lipoprotein in healthy adults, overweight individuals, and smokers [39].

Grapes also provide multiple benefits for the eyes. For instance, a study conducted by Amit et al. demonstrated that grape intake improves photoreceptor survival and preserves visual function in a mouse model of retinal degeneration [40]. Moreover, another research group demonstrated that a diet rich in grapes inhibits the formation of new blood vessels in a choroidal neovascularization model [41]. However, the potential therapeutic advantages of grapes, especially in the context of cataract prevention, have yet to be extensively investigated. In this study, we investigated whether grape powder (GP), the freeze-dried powder of fresh grapes, could inhibit the onset and progression of cataract formation. We used a UV radiation-induced cataract mouse model to examine the effects. To gain a deeper understanding of the molecular mechanisms involved in cataract prevention, we employed a systemic pharmacology approach to identify the primary molecular targets of grapes within the lens.