Age-related macular degeneration (AMD) is categorized into two types: wet and dry. Wet AMD is characterized by the development of anomalous blood vessels beneath the retina, while dry AMD is marked by drusen accumulation and the atrophy of retinal pigment epithelial (RPE) cells. While there are available treatments for wet AMD, there is no established remedy for dry AMD, which constitutes approximately 85–90% of all cases of AMD. Furthermore, dry AMD is a leading cause of irreversible vision loss and blindness among the elderly population worldwide, recent statistics indicated its prevalence in over 196 million individuals as of 2020, with projections surging to 288 million by 2040.(Guymer and Campbell, 2023; Chen et al., 2023).

Oxidative stress is considered a primary factor contributing to the development and progression of dry AMD.(Hollyfield et al., 2008; Shaw et al., 2016) The retina is particularly susceptible to oxidative damage owing to its high metabolic activity, high oxygen consumption, and abundant polyunsaturated fatty acid levels.(Courtie et al., 2020) The accumulation of reactive oxygen species (ROS) in the retina can lead to the dysfunction and death of RPE cells, which in turn contributes to drusen formation and the development of dry AMD. Reactive oxygen species (ROS) can damage RPE cells and photoreceptors in the macula through lipid peroxidation, protein oxidation, and DNA damage.(Kaarniranta et al., 2020; Fisher and Ferrington, 2018).

Antioxidants were proposed as potential therapeutic agents considering the role of oxidative stress in the pathogenesis of dry AMD. However, clinical trials with commonly used antioxidants such as Vitamin C and E show limited benefits(Age-Related Eye Disease Study Research Group, 2001). Many antioxidants have poor bioavailability since they are not easily absorbed or distributed throughout the body. For example, numerous studies demonstrate that resveratrol is effective against various eye diseases. However, human pharmacokinetic evaluations show that trans-resveratrol (RSV) has a notably low serum concentration post oral and intraperitoneal administration.(Abu-Amero et al., 2016) A crucial factor to consider is its bioavailability, which is below 1%, largely owing to its fast metabolism in the liver and intestine.(Goldberg et al., 2003) The challenges with RSV usage in vivo can be attributed to its quick absorption, limited bioavailability, and poor water solubility. (Walle et al., 2004; Ferraz da Costa et al., 2020).

Additionally, some antioxidants are not specifically targeted to the eye, which is the site of AMD. This can lead to systemic side effects and suboptimal delivery to the affected tissues. Furthermore, some antioxidants tested in clinical trials show limited benefits or harmful effects in certain cases. For instance, high doses of beta-carotene, antioxidant are associated with an increased risk of lung cancer in smokers(Goralczyk, 2009; Druesne-Pecollo et al., 2010). Therefore, there is a need for novel antioxidant therapies that can overcome these limitations and offer targeted and effective treatments for dry AMD.

L-Ergothioneine (EGT) is a naturally occurring amino acid and potent antioxidant found in mushrooms and black garlic. It accumulates in high concentrations in certain tissues, including ocular tissues, such as the lens, retina, cornea, and RPE.(Shires et al., 1997) Furthermore, elevated levels of OCTN1 mRNA encoding the EGT transporter(Gründemann et al., 2005) were observed in the eyes of different species, including pigs,(Shires et al., 1997) and zebrafish.(Pfeiffer et al., 2015) In humans, EGT is present in tears and the aqueous humor, suggesting its potential role in protecting the eye against oxidative damage.(Shires et al., 1997) Conversely, decreased EGT levels may increase susceptibility to ocular disorders, as shown by the notable decrease in EGT levels in the human eye lens as cataract severity increases.(Shukla et al., 1982) Low plasma or whole-blood levels of EGT correlate with an increased risk of macular degeneration.(Halliwell et al., 2023) L-Ergothioneine may play a protective role in AMD. It has protective effects on corneal endothelial cells from hydrogen peroxide (H2O2)-induced oxidative stress and the unfolded protein response.(Kim et al., 2017) However, few studies have investigated the protective effects of EGT against AMD and other ocular diseases.

This study screened a library of antioxidants and identified EGT as a potent cytoprotective agent, which was verified by a series of in vitro and in vivo experiments. Additionally, we found that EGT maintained the structural and functional stability of cells and tissues and the normal physiological function of mice. Furthermore, transcriptomic analysis revealed that EGT counteracted the major gene expression changes induced by oxidative stress. It also upregulated antioxidant genes and inhibited NRF2 translocation. These findings suggest that EGT may represent a novel therapeutic strategy for treating dry AMD and providing an impetus for further investigation of this compound in clinical trials.