Zhang Yifei, Li Junfang, Zhang Yu, Qu Yi
Department of Geriatrics, Qilu Hospital of Shandong University, Jinan 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan 250012, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan 250012, China.
Department of Geriatrics, Qilu Hospital of Shandong University, Jinan 250012, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan 250012, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan 250012, China.
Methods. 2025 Oct;242:187-199. doi: 10.1016/j.ymeth.2025.08.001. Epub 2025 Aug 6.
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.
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.
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.
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.
葡萄膜黑色素瘤是成人中最常见的原发性眼内恶性肿瘤，其特征是患者间存在显著异质性且长期预后较差。铁死亡是一种铁依赖性的程序性细胞死亡形式，已成为癌症治疗的一个有前景的途径，但其在葡萄膜黑色素瘤中的作用仍未得到充分研究。
我们通过整合单变量Cox回归、LASSO回归和随机森林算法，系统筛选了与葡萄膜黑色素瘤预后相关的铁死亡相关基因（FRGs）。使用来自癌症基因组图谱和基因表达综合数据库队列的数据构建并验证了一个预后特征。我们进一步评估了该模型与临床病理特征、肿瘤免疫微环境和药物敏感性的关联。进行体外实验以验证特征中最关键的基因SIRT3的功能作用。
开发了一个基于FRG的强大预后模型，该模型包含SIRT3、RRM2和PANX2，并成功将患者分为高风险和低风险组，两组的生存结果有显著差异。多变量Cox回归证实风险评分是一个独立的预后因素。高风险患者表现出免疫抑制性微环境特征，包括调节性T细胞升高和巨噬细胞浸润增加，以及对免疫检查点阻断的预测反应较低。药物敏感性分析确定了高风险组中预测IC50值较低的十种化合物，表明其具有潜在的治疗相关性。功能测定表明，SIRT3基因敲低促进了葡萄膜黑色素瘤细胞的增殖和迁移，同时减弱了对铁死亡的敏感性，突出了其肿瘤抑制作用。
本研究提出了一种在葡萄膜黑色素瘤中具有强大预后和免疫学意义的新型FRG特征。该模型为风险分层提供了一个有前景的工具，并可能有助于指导基于铁死亡和免疫治疗的精准治疗。我们的研究结果还表明，SIRT3在葡萄膜黑色素瘤中作为铁死亡敏化剂发挥作用，是一个值得进一步研究的潜在治疗靶点。
