Natural Compound Veratrine Shows Promise Against ER Stress in Corneal Endothelial Cells

Researchers at the Icahn School of Medicine at Mount Sinai have completed a systematic screen of 502 natural compounds, searching for readily available botanical and botanical-derived molecules that can protect corneal endothelial cells from endoplasmic reticulum stress, a key driver of cell death in Fuchs endothelial corneal dystrophy. The study, published in Frontiers in Ophthalmology, identified veratrine, a steroidal alkaloid from Veratrum plants, as a lead candidate that suppressed all three arms of the unfolded protein response and reduced apoptotic signaling in a diseased corneal endothelial cell model.

Corneal endothelial cells form the thin inner lining of the cornea and are responsible for pumping fluid out of the corneal stroma, keeping the tissue transparent. Unlike most cells in the body, they do not divide meaningfully in adults, so their loss is permanent. In Fuchs endothelial corneal dystrophy, one of the most common indications for corneal transplantation, sustained endoplasmic reticulum stress leads to mitochondrial dysfunction and apoptotic cell death, progressively depleting the endothelial layer and causing corneal swelling and vision loss.

The research team, led by first authors Stephanie Churchill, Anika Kulkarni, and Min Kwon in the laboratory of senior investigator Dr. Vivek Kulkarni, reasoned that natural compounds, which have significant pharmacological activities and have been studied in diabetes, retinopathy, and glaucoma, might offer protective effects against sustained endoplasmic reticulum stress in corneal endothelial cells. Prior work by the group had shown that an endoplasmic reticulum chaperone, 4-phenylbutyrate, could prevent mitochondrial dysfunction in stressed corneal endothelial cells, supporting the idea that targeting the stress response could be therapeutic.

To test this systematically, the researchers used an immortalized corneal endothelial cell line, 21T-HCEnC, and screened the 502-compound natural product library at a fixed dose of 10 micromolar. Each compound was applied as a pretreatment two hours before the cells were exposed to tunicamycin, a well-established inducer of endoplasmic reticulum stress that blocks protein folding in the endoplasmic reticulum. Cell viability was measured after 24 hours using the CellTiter-Glo assay, which quantifies cellular ATP as a proxy for metabolic activity and survival.

The primary screen identified 15 compounds that increased cell viability by more than 20 percent under tunicamycin-induced stress. The researchers then performed a secondary validation screen, confirming the protective effects of the top candidates and measuring their dose-response relationships. Among the validated hits, veratrine stood out for its potency and its established pharmacological profile. Veratrine is a mixture of steroidal alkaloids, primarily cevadine and veratridine, derived from the seeds of Veratrum plants, and has been used historically as an antihypertensive and anticonvulsant agent.

To characterize the mechanism of veratrine in detail, the researchers performed a series of experiments in a diseased corneal endothelial cell model. They measured the activation of the three arms of the unfolded protein response, including PERK, IRE1, and ATF6, using Western blotting and quantitative PCR. They also measured apoptotic signaling, including cleaved caspase-3 and cleaved PARP, and mitochondrial function, including cytochrome c release and mitochondrial membrane potential. The results showed that veratrine suppressed all three arms of the unfolded protein response and reduced apoptotic signaling in the diseased cell model.

The researchers also explored the relationship between veratrine and sodium channels, which are the established molecular targets of veratridine, one of the two principal components of veratrine. Veratridine binds to voltage-gated sodium channels and causes persistent activation, leading to sodium influx and depolarization. The researchers found that veratrine modulated sodium channel activity in corneal endothelial cells, suggesting that the protective effects might be related to channel modulation rather than persistent activation.

The study also identified three other validated hits, including ginkgolide B, baicalein, and ginsenoside Rg1, which showed protective effects in the primary and secondary screens. Ginkgolide B is a diterpene lactone from Ginkgo biloba, baicalein is a flavonoid from Scutellaria baicalensis, and ginsenoside Rg1 is a triterpene saponin from Panax ginseng. All three compounds have established pharmacological profiles and have been studied in various disease models, supporting the idea that natural compounds might offer therapeutic effects against endoplasmic reticulum stress in corneal endothelial cells.

The researchers acknowledge several limitations of the study. The experiments were performed in an immortalized cell line rather than primary corneal endothelial cells, and the protective effects of veratrine were measured under acute stress rather than chronic disease conditions. The researchers also note that veratrine has a narrow therapeutic window, and its safety profile in corneal endothelial cells has not been established. Further studies are needed to validate the protective effects of veratrine in primary cells and animal models, and to establish its safety profile for potential therapeutic use.

Despite these limitations, the study represents a significant advance in the search for natural compounds that can protect corneal endothelial cells from endoplasmic reticulum stress. The identification of veratrine as a lead candidate, along with three other validated hits, provides a foundation for further research into natural compounds as therapeutic agents against Fuchs endothelial corneal dystrophy and other corneal endothelial diseases. The researchers hope that their findings will inspire further studies into natural compounds as therapeutic agents against corneal endothelial diseases, and that the protective effects of veratrine might be validated in primary cells and animal models for potential therapeutic use.

Subject of Research: Screening of natural compounds library for protection against endoplasmic reticulum stress in corneal endothelial cells

Article Title: Screening of natural compounds library for protection against endoplasmic reticulum stress in corneal endothelial cells

Article References: Lee, S., Kasi, A., Kwon, M., Kim, S. Y., Qureshi, S., & Kumar, V. (2026). Screening of natural compounds library for protection against endoplasmic reticulum stress in corneal endothelial cells. Frontiers in Ophthalmology, 6, Article 1945775. https://doi.org/10.3389/fopht.2026.1945775

Image Credits: AI Generated

DOI: 10.3389/fopht.2026.1945775

Keywords: Screening, natural, compounds, library, protection, against, endoplasmic, reticulum, stress, corneal, endothelial, cells