Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.

上皮间质转化 (EMT) 是发育和伤口愈合的重要机制，但在癌症中，它还介导侵袭性肿瘤的进展和扩散，同时增加治疗抵抗力。间充质状态的采用也与铁摄取增加有关，但 EMT 与细胞铁代谢的关键调节剂之间的关系仍未确定。在这方面，人肾上腺皮质癌 SW13 细胞系代表了一种宝贵的研究模型，因为 HDAC 抑制剂治疗可以将它们从上皮样 (SW13-) 细胞类型转变为间充质样 (SW13+) 亚型。在这项研究中，我们建立了 SW13 细胞作为探索铁和 EMT 之间联系的模型。HDAC 抑制剂介导的 EMT 后铁积累增加与铁输出蛋白 ferroportin 的表达减少、ROS 产生增加和抗氧化反应基因的表达减少有关。由于氧化还原活性铁的可用性和脂质过氧化物修复能力的丧失是铁死亡（一种铁介导的细胞死亡形式）的标志，我们接下来检查了 HDAC 抑制剂治疗是否可以增加铁死亡的敏感性。事实上，HDAC 抑制剂治疗在诱导铁死亡后协同增加了细胞死亡。HDAC抑制促进铁死亡诱导后细胞死亡的确切机制需要进一步研究。由于几种 HDAC 抑制剂已经在临床上用于治疗某些癌症类型，