Eriocitrin inhibits sodium iodate-induced cuproptosis and barrier function impairment in retinal pigment epithelium via SIRT7/YAP/ATP7A pathway.

BACKGROUND: Dry age-related macular degeneration (AMD) is characterized by retinal pigment epithelium (RPE) barrier dysfunction, and currently lacks effective treatment options. Eriocitrin is a natural flavonoid with antioxidant and anti-inflammatory properties, and its potential role in inhibiting cuproptosis and improving RPE barrier function remains unclear. METHODS: ARPE-19 cells treated with sodium iodate (NaIO₃) were used to establish an in vitro AMD model. The effects of eriocitrin at various concentrations (0-100 µM) and treatment durations on cell viability were assessed using the CCK-8 assay. ELISA and ROS fluorescence were used to assess inflammation and oxidative stress levels. Western blotting and qPCR analysis were employed to evaluate the expression of copper-dependent programmed cell death (cuproptosis)-related markers. RPE barrier function was analyzed by transepithelial electrical resistance (TEER), FITC-dextran permeability assays, and the expression of tight junction proteins. We further utilized siRNA to knockdown SIRT7 and ATP7A gene, and pharmacological inhibition of YAP using verteporfin. In vivo, a NaIO₃-induced AMD model was established in both C57BL/6J and SIRT7 silencing mice, followed by administration of eriocitrin (25 or 50 mg/kg). Retinal histology and protein expression were subsequently analyzed. RESULTS: Eriocitrin significantly ameliorated NaIO₃-induced reductions in cell viability, decreased ROS levels, and suppressed inflammatory cytokine expression. It also restored RPE barrier function in a dose-dependent manner. Mechanistically, eriocitrin modulated SIRT7 expression, inhibited YAP activity, and enhanced ATP7A expression. Genetic silencing or knockdown of SIRT7 markedly weakened the protective effects of eriocitrin, including its antioxidant and barrier-restoring functions. YAP inhibition by verteporfin partially mimicked the actions of eriocitrin, while ATP7A silencing completely abrogated its effects, indicating that the SIRT7/YAP/ATP7A axis plays a crucial role in the therapeutic mechanism of eriocitrin against AMD. CONCLUSION: This study demonstrated that eriocitrin alleviates NaIO₃-induced oxidative stress and RPE barrier dysfunction by modulating the SIRT7/YAP/ATP7A signaling pathway and inhibiting cuproptosis. Our findings indicated eriocitrin as a promising natural therapeutic candidate for dry AMD and lay the foundation for developing flavonoid-based anti-cuproptosis strategies.