Sep 2026· International Journal of Ophthalmology· Vol 19 9, pp.
1667-1675
· 0 citations
Medicine
TL;DR
Findings provide the first evidence that FUNDC2 acts as a potential upstream regulator of RPE ferroptosis in RP, at least partially by negatively regulating GPX4.
Abstract
Aim
To investigate the key role of the mitochondrial outer membrane protein FUN14 domain-containing 2 (FUNDC2) in retinal pigment epithelium (RPE) ferroptosis during retinitis pigmentosa (RP) progression.
Methods
Unbiased label-free proteomics was employed to identify differentially expressed proteins in the RPE of a sodium iodate (SI)-induced rat model. In vitro experiments were conducted using human retinal pigment epithelial (ARPE)-19 cells. The effects of SI treatment and FUNDC2 knockdown on cell viability and the expression of ferroptosis-protective molecules, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 25 member 11 (SLC25A11) were evaluated.
Results
Proteomic analysis revealed that FUNDC2 was significantly upregulated in the RPE of SI-induced rats. In ARPE-19 cells, SI treatment significantly increased FUNDC2 expression while decreasing the levels of ferroptosis-protective molecules. Functional experiments demonstrated that knocking down FUNDC2 effectively rescued SI-induced loss of cell viability and restored GPX4 expression.
Conclusion
These findings provide the first evidence that FUNDC2 acts as a potential upstream regulator of RPE ferroptosis in RP, at least partially by negatively regulating GPX4. Consequently, FUNDC2 is a potential therapeutic target for the future treatment of RP.
Functional investigations revealed that Nrf2 positively regulates FTL at the transcriptional level, establishing a critical "Nrf2-FTL-iron metabolism" regulatory axis that suppresses ferroptosis susceptibility by coordinately maintaining iron homeostasis and redox balance.
A posttranscriptional regulation of FTH1 by RSL1D1 is unveiled and the implication of RSL1D1/FTH1 in cellular senescence and ferroptosis in diabetic retinopathy in DR is uncovered.
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Bisphenol A (BPA), a widespread environmental endocrine disruptor, is associated with neurodevelopmental disorders and induces oxidative neurotoxicity. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has been implicated in toxicant‑induced neuronal injury. However, whether BPA triggers neuronal ferroptosis through autophagy remains unclear. Using HT‑22 hippocampal neuronal cells as an in vitro model, we investigated the role of autophagy‑dependent ferroptosis in BPA neurotoxicity. BPA exposure caused oxidative damage and mitochondrial ultrastructural abnormalities. It also induced ferroptosis‑related changes, including increased malondialdehyde (MDA), prostaglandin endoperoxide synthase 2 (PTGS2) protein expression, and reactive oxygen species (ROS), as well as decreased glutathione (GSH), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). These effects were reversed by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO). Pharmacological inhibition of autophagy with chloroquine (CQ) also reversed BPA-induced GPX4/SLC7A11 downregulation and PTGS2 upregulation. Notably, BPA decreased the expressions of nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1), which was blocked by CQ. Knockdown of NCOA4 attenuated BPA-induced FTH1 and GPX4 loss, and PTGS2 elevation, indicating that NCOA4-mediated ferritinophagy is required for BPA-induced ferroptosis. Mechanistically, BPA activated AMPK/ULK1 axis while inhibiting mTOR; silencing of AMPK or ULK1 partially abrogated BPA-induced autophagy and ferroptosis. Collectively, these findings demonstrate that BPA activates the AMPK/mTOR/ULK1 signaling pathway to promote NCOA4‑mediated ferritinophagy, leading to ferroptosis in HT‑22 cells. This study provides a novel insight into the molecular mechanisms underlying BPA-associated neurotoxicity.
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