A newly developed ferroptosis-related gene signature for forecasting prognosis in uveal melanoma.

Background: Uveal melanoma is the most common primary intraocular malignancy in adults, characterized by significant inter-patient heterogeneity and poor long-term prognosis. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising avenue for cancer therapy, yet its role in UVM remains insufficiently explored.

Methods: We systematically screened ferroptosis-related genes (FRGs) associated with UVM prognosis by integrating univariate Cox regression, LASSO regression, and Random Forest algorithms. A prognostic signature was constructed and validated using data from The Cancer Genome Atlas and Gene Expression Omnibus cohorts. We further evaluated the model's association with clinicopathological features, tumor immune microenvironment, and drug sensitivity. In vitro experiments were conducted to validate the functional role of SIRT3, the most pivotal gene in the signature.

Results: A robust FRG-based prognostic model comprising SIRT3, RRM2, and PANX2 was developed and successfully stratified patients into high- and low-risk groups with significantly different survival outcomes. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. High-risk patients exhibited immunosuppressive microenvironmental features, including elevated regulatory T cells and macrophage infiltration, as well as lower predicted response to immune checkpoint blockade. Drug sensitivity analysis identified ten compounds with lower predicted IC50 values in the high-risk group, suggesting potential therapeutic relevance. Functional assays demonstrated that SIRT3 knockdown promoted UVM cell proliferation and migration, while attenuating susceptibility to ferroptosis, highlighting its tumor-suppressive role.

Conclusion: This study presents a novel FRG signature with strong prognostic and immunological implications in UVM. The model offers a promising tool for risk stratification and may assist in guiding ferroptosis- and immunotherapy-based precision treatment. Our findings also suggest that SIRT3 acts as a ferroptosis sensitizer in UVM, representing a potential therapeutic target warranting further investigation.