Ferroptosis dysregulation, mitochondrial dysfunction, and iron metabolism alterations are correlated with...

To elucidate the dysregulation of ferroptosis in uveal melanoma (UM), a comprehensive understanding is required of the expression patterns of ferroptosis-related genes, their association with key driver mutations and clinicopathological features, and their prognostic significance in UM patients. We analyzed tumor tissues from 56 UM enucleated eyeballs using qRT-PCR, immunohistochemistry, and western blotting to quantify ferroptosis-associated genes (SLC7A11, SLC3A2, GPX4, TFR1, CISD1, ACSL4, LPCAT3). Serum glutathione (GSH), ferritin, and lipid peroxidation assays were performed. These data were integrated with clinicopathologic parameters, driver mutations, mitochondrial ultrastructure, mtDNA copy number, and clinical outcomes. Independent validation was performed using TCGA-UM data. SLC7A11 and GPX4 were significantly upregulated in BAP1-mutant tumors. High expression of these markers was associated with reduced metastasis-free and overall survival (p < 0.05). TFR1 was downregulated in BAP1-deficient tumors, and low TFR1 protein levels independently predicted poor prognosis (p < 0.01). Serum GSH was decreased in UM patients, despite upregulation of GSH-related genes, indicating systemic oxidative imbalance. Downregulation of CISD1, ACSL4, and LPCAT3 were linked to alteration in mitochondria morphology, elevated mtDNA content, and unfavorable prognosis. These findings indicate that ferroptosis dysregulation is a hallmark of aggressive UM. SLC7A11, GPX4, and TFR1 represent clinically relevant biomarkers and potential therapeutic targets.