组蛋白甲基转移酶在非小细胞肺癌（NSCLC）的发展中起着关键调控作用。本研究探讨了组蛋白甲基转移酶含有1A结构域（SETD1A）介导的H3K4me2甲基化在NSCLC细胞铁死亡中的机制，并为NSCLC治疗提供了新的靶点。通过SETD1A在NSCLC细胞系中的下调，使用细胞计数试剂盒、ELISA、铁含量试剂盒、RT-qPCR和蛋白质免疫印迹等方法，测定了细胞增殖潜力、丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）活性、铁含量以及SETD1A、长链非编码RNA HOXC簇反义RNA 3（lncRNA HOXC-AS3）、E1A结合蛋白p300（EP300）、谷胱甘肽过氧化物酶4（GPX4）的表达。采用染色质免疫沉淀法测定HOXC-AS3启动子中SETD1A和H3K4me3的富集水平，通过RNA免疫沉淀分析HOXC-AS3与EP300的结合。还进行了救治实验以确认它们在NSCLC细胞铁死亡中的作用。建立移植瘤模型以验证SETD1A在体内的作用。NSCLC细胞中SETD1A、H3K4me3、HOXC-AS3和EP300表达高。沉默SETD1A抑制了NSCLC细胞的增殖，增加了MDA和铁水平，降低了SOD、GSH和GPX4的水平。SETD1A下调降低了H3K4me3水平、HOXC-AS3表达、HOXC-AS3与EP300的结合以及EP300的稳定性。HOXC-AS3或EP300的过表达逆转了SETD1A沉默对NSCLC细胞铁死亡的促进作用。SETD1A沉默降低了肿瘤体积和重量，提高了ki67阳性率，并通过HOXC-AS3/EP300轴增加了铁死亡。SETD1A介导的H3K4me2甲基化促进HOXC-AS3表达，HOXC-AS3与EP300的结合以及EP300的稳定性，从而抑制NSCLC细胞的铁死亡。© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Histone methyltransferases are crucial regulators in non-small cell lung cancer (NSCLC) development. This study explored the mechanism of histone methyltransferase SET domain containing 1A (SETD1A)-mediated H3K4me2 methylation in NSCLC cell ferroptosis and provides novel targets for NSCLC treatment.Upon downregulation of SETD1A in NSCLC cell lines, cell proliferation potential, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) activities, iron content, and SETD1A, long noncoding RNA HOXC cluster antisense RNA 3 (lncRNA HOXC-AS3), E1A binding protein p300 (EP300), glutathione peroxidase 4 (GPX4) expressions were determined via cell counting kit-8, ELISA, iron assay kits, RT-qPCR, and western blot. Enrichment levels of SETD1A and H3K4me3 in the HOXC-AS3 promotor were measured via chromatin immunoprecipitation, and the binding of HOXC-AS3 and EP300 was analyzed via RNA immunoprecipitation. Rescue experiments were performed to confirm their roles in NSCLC cell ferroptosis. Xenograft tumor models were established to validate the role of SETD1A in vivo.SETD1A, H3K4me3, HOXC-AS3, and EP300 were highly-expressed in NSCLC cells. Silencing SETD1A inhibited NSCLC cell proliferation, increased MDA and iron levels, and decreased SOD, GSH, and GPX4 levels. SETD1A downregulation reduced H3K4me3 level, HOXC-AS3 expression, the binding of HOXC-AS3 to EP300, and EP300 stability. Overexpression of HOXC-AS3 or EP300 reversed the promotion of silencing SETD1A on NSCLC cell ferroptosis. Silencing SETD1A reduced tumor volume and weight and positive rate of ki67 and increased ferroptosis through the HOXC-AS3/EP300 axis.SETD1A-mediated H3K4me2 methylation promoted HOXC-AS3 expression, binding of HOXC-AS3 to EP300, and EP300 stability, thereby suppressing NSCLC cell ferroptosis.© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.