Background/Objectives: Mesothelioma is a highly aggressive tumor with a poor prognosis that typically develops after a long latency period following asbestos exposure. Although immunotherapy combined with chemotherapy is increasingly used, the efficacy of standard treatments remains limited. This study aimed to explore ferroptosis induction as a potential therapeutic strategy for mesothelioma.Methods: We first screened microbial culture extracts collected from soil and marine environments to identify compounds with selective cytotoxicity against mesothelioma cells. Gene expression profiling was performed to investigate the mechanism of cell death induced by the identified compound. To assess intrinsic ferroptosis susceptibility, patient-derived mesothelioma cell lines and immortalized mesothelial cell lines were treated with RSL3, a GPX4 inhibitor.Results: Screening identified brefeldin A as a compound that selectively induces cell death in mesothelioma cells. Gene expression profiling revealed transcriptional changes consistent with ferroptosis induction. Treatment with RSL3 demonstrated marked variability in ferroptosis sensitivity across cell lines; the subgroup showing high sensitivity to RSL3 did not exhibit significant genetic alterations inNF2orBAP1, but contained a significantly higher proportion of epithelioid tumors in histological classification.Conclusions: Our findings highlight ferroptosis induction as a promising antitumor mechanism in mesothelioma, particularly in the epithelioid subtype. While GPX4 inhibitors such as RSL3 are effective in vitro, further studies are needed to overcome pharmacological limitations and define molecular determinants of ferroptosis susceptibility, which may inform future personalized therapeutic strategies.
**背景/目的：** 间皮瘤是一种高度侵袭性肿瘤，预后不良，通常在石棉暴露后经历较长潜伏期发病。尽管免疫疗法联合化疗的应用日益增多，但标准治疗的疗效仍然有限。本研究旨在探讨诱导铁死亡作为间皮瘤潜在治疗策略的可能性。 **方法：** 我们首先筛选了从土壤和海洋环境中收集的微生物培养物提取物，以鉴定对间皮瘤细胞具有选择性细胞毒性的化合物。通过基因表达谱分析来研究所鉴定化合物诱导细胞死亡的机制。为了评估内在的铁死亡易感性，使用GPX4抑制剂RSL3处理了来源于患者的间皮瘤细胞系和永生化间皮细胞系。 **结果：** 筛选鉴定出布雷菲德菌素A是一种能选择性诱导间皮瘤细胞死亡的化合物。基因表达谱分析揭示了与铁死亡诱导一致的转录变化。RSL3处理显示，不同细胞系对铁死亡的敏感性存在显著差异；对RSL3表现出高敏感性的亚组，在NF2或BAP1基因上未表现出显著的遗传学改变，但在组织学分类中，上皮样肿瘤的比例显著更高。 **结论：** 我们的研究结果强调了诱导铁死亡是间皮瘤，尤其是上皮样亚型中一种有前景的抗肿瘤机制。虽然RSL3等GPX4抑制剂在体外有效，但需要进一步研究以克服药理学限制，并明确铁死亡易感性的分子决定因素，这可能为未来的个体化治疗策略提供信息。
肿瘤(癌症)患者之家