Mitochondrial outer membrane protein FUNDC2 contributes to ferroptosis as a potential upstream regulator in retinitis pigmentosa.

Ferritin Light Chain: A Key Regulator of Nrf2-Dependent Ferroptosis in Oral Squamous Cell Carcinoma.

OBJECTIVE Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of ferroptosis, and ferritin light chain (FTL) plays a central role in iron metabolism and is actively involved in the ferroptotic process. However, the mechanism by which Nrf2 may modulate ferroptosis in oral squamous cell carcinoma (OSCC) through the regulation of FTL remains poorly understood. This study aims to investigate the molecular mechanisms underlying Nrf2-mediated regulation of ferroptosis via FTL in OSCC cell lines SCC-25 and CAL-27, with the goal of providing new insights into the ferroptosis regulatory network in OSCC. METHODS The expression profiles of Nrf2 and FTL were initially characterized in OSCC tissues and matched adjacent normal tissues, with subsequent correlation analysis against clinicopathological parameters. To investigate their functional roles, Nrf2 and FTL expression was silenced using siRNA technology in combination with ferroptosis inhibitor Fer-1 treatment. Cellular viability was determined by CCK-8 assay, while ferroptosis was assessed by measuring intracellular Fe2+ concentrations and MDA content. Quantitative assessment of lipid peroxidation was performed with flow cytometry. Protein expression patterns of Nrf2, FTL, and downstream ferroptosis regulators (GPX4, FSP1, and ACSL4) were analyzed by Western blot. The regulatory function of the Nrf2-FTL axis in ferroptosis was further validated through complementary gene knockdown and overexpression experiments. RESULTS Molecular analyses demonstrated significant upregulation of Nrf2 and FTL expression in both OSCC tissues and cell lines, with Nrf2 expression levels showing a strong correlation with lymph node metastasis and advanced T-stage (T3-T4a). Functional investigations revealed that Nrf2 positively regulates FTL at the transcriptional level, establishing a critical "Nrf2-FTL-iron metabolism" regulatory axis. Genetic silencing experiments demonstrated that knockdown of either Nrf2 or FTL synergistically reduced cell viability, induced iron accumulation, increased lipid peroxidation, and altered ferroptosis-related protein expression-effects that were partially rescued by the ferroptosis inhibitor Fer-1. Mechanistically, this regulatory axis suppresses ferroptosis susceptibility by coordinately maintaining iron homeostasis and redox balance. Notably, Nrf2 overexpression could counteract the enhanced ferroptosis resulting from FTL knockdown, unequivocally establishing the central role of the Nrf2-FTL axis in regulating ferroptosis in OSCC. CONCLUSION The Nrf2-FTL axis positively regulates FTL at the transcriptional level and modulates iron metabolism and oxidative stress pathways, thereby inhibiting ferroptosis susceptibility in OSCC cells.

RSL1D1 deficiency reduces FTH1 stability and induces ferroptosis and senescence in retinal pigment epithelial cells in diabetic retinopathy.

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.

Activation of ER stress mediated by HspB4/Cryaa reduction contributes to photoreceptor apoptosis in rd9 mouse model of X-linked Retinitis Pigmentosa

Results identify Cryaa as a critical regulator of ER stress and demonstrate that its reduction promotes UPR activation and subsequent photoreceptor apoptosis in the rd9 model, revealing a key role for Cryaa in XLRP pathology and may provide a novel therapeutic perspective for this disease.

Endolysosomal iron-associated vesicular changes and ferroptosis-related vulnerability in VPS13A-knockdown cells

AMPK/mTOR/ULK1 Signaling Mediates NCOA4-Dependent Ferritinophagy in BPA-Induced Ferroptosis in HT-22 Hippocampal Neuronal Cells.

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.

FOXO6 inhibits SMURF2‐mediated ubiquitination and degradation of NR4A1 to promote retinal pigment epithelial cell ferroptosis in diabetic retinopathy

Abstract Diabetic retinopathy (DR) is the main cause of vision loss, with retinal pigment epithelial (RPE) cell dysfunction as a key contributor. Ferroptosis is implicated in RPE injury under hyperglycemia; however, its upstream regulatory mechanisms remain unclear. High glucose (HG)‐induced human RPE ARPE‐19 cells and a diabetic mouse model were used. Ferroptosis was assessed through biochemical assays, Western blot, fluorescence probes, and histological staining. Protein interactions and transcriptional regulation were examined using Co‐IP, glutathione S‐transferase pull‐down, ChIP, and luciferase reporter assays. Immunofluorescence staining was used as key indicator expression in retinal tissues. Nuclear receptor 4A1 (NR4A1) expression was upregulated under HG‐induced ARPE‐19 cells. NR4A1 knockdown alleviated HG‐induced iron accumulation, lipid peroxidation, and ferroptosis marker changes. Mechanistically, SMAD‐specific E3 ubiquitin protein ligase 2 (SMURF2) interacted with NR4A1 and promoted its ubiquitination and degradation. Forkhead box O6 (FOXO6) was upregulated by HG and repressed SMURF2 transcription. SMURF2 overexpression mitigated HG‐induced ARPE‐19 ferroptosis and retinal injury in DR mice, an effect reversed by NR4A1 co‐overexpression. SMURF2 knockdown reversed the effect of FOXO6 knockdown on HG‐induced ferroptosis in ARPE‐19 cells and retinal injury in DR mice. The FOXO6–SMURF2–NR4A1 axis critically regulates ferroptosis in RPE cells during DR.