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Salidroside alleviates ferroptosis in FAC-induced Age-related macular degeneration models by activating
1Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China.
Introduction:
Age-related macular degeneration (AMD) is a significant contributor to irreversible impairment in visual capability, particularly in its non-neovascular (dry) form. Ferroptosis, an emerging form of programmed necrosis, involves generating lipid peroxidation (LOS) through free iron and reactive oxygen species (ROS). Salidroside, a glycoside from Rhodiola rosea, known for anti-inflammatory and antioxidant properties. The research aim was exploring whether ferroptosis exists in dry AMD pathogenesis and elucidate salidroside's protective mechanisms against ferroptosis in AMD murine models and ARPE-19 cells.
Methods:
ARPE-19 cells were treated with varying concentrations of ferrous ammonium citrate (FAC) and salidroside. In an in vivo model, C57BL/6 mice were administered intraperitoneal injections of salidroside for 7 consecutive days, followed by an intravitreal injection (IVT) of FAC. After 7 days, the eyeballs were harvested for subsequent analyses. Ferroptosis markers were assessed using western blotting, immunofluorescence staining, and flow cytometry. To further elucidate the modulatory role of Nrf2 in ferroptosis, ARPE-19 cells were transfected with si-Nrf2.
Results:
In vitro, FAC-treated ARPE-19 cells exhibited reduced viability, decreased mitochondrial membrane potential (MMP), and accumulation of iron and lipid peroxidation (LOS) products. In vivo, FAC administration by IVT led to outer nuclear layer thinning and compromised tight junctions in RPE cells. The GPX4, Nrf2, and SLC7A11 expressions were downregulated both in vitro and in vivo. Salidroside upregulated Nrf2 and ameliorated these outcomes, but its effects were attenuated in ARPE-19 cells transfected with si-Nrf2.
Conclusion:
Our study establishes that FAC induces RPE cell ferroptosis within dry AMD, and salidroside exerts therapeutic effects by triggering Nrf2/SLC7A11/GPX4 signaling axis.
Insights
Ferroptosis contributes to dry age-related macular degeneration (AMD). Salidroside protects against ferroptosis by activating the Nrf2/SLC7A11/GPX4 pathway, offering a potential therapeutic strategy for dry AMD.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- Dry age-related macular degeneration (AMD) causes irreversible vision loss.
- Ferroptosis, a cell death pathway involving iron and lipid peroxidation, is implicated in dry AMD pathogenesis.
- Salidroside, a natural compound, possesses antioxidant and anti-inflammatory properties.
Purpose of the Study:
- To investigate the role of ferroptosis in dry AMD.
- To explore the protective mechanisms of salidroside against ferroptosis in dry AMD models.
Main Methods:
- ARPE-19 cells and C57BL/6 mice models were used.
- Ferroptosis was induced using ferrous ammonium citrate (FAC).
- Salidroside treatment and Nrf2 gene silencing were performed. Biomarkers were analyzed via western blotting, immunofluorescence, and flow cytometry.
Main Results:
- FAC induced ferroptosis in ARPE-19 cells and RPE cells in mice, evidenced by decreased viability, mitochondrial potential, and altered ferroptosis markers.
- Salidroside treatment reversed these effects by upregulating Nrf2, SLC7A11, and GPX4.
- Nrf2 silencing diminished salidroside's protective effects.
Conclusions:
- Ferrous ammonium citrate induces ferroptosis in retinal pigment epithelium (RPE) cells, contributing to dry AMD.
- Salidroside demonstrates therapeutic potential for dry AMD by activating the Nrf2/SLC7A11/GPX4 signaling pathway.
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