肺癌细胞过度表达黏液蛋白1（MUC1）和活性亚单位MUC1-CT。虽然肽可以阻止MUC1信号，但对靶向MUC1的代谢产物的研究还不充分。AICAR是一种嘌呤生物合成中间体。AICAR处理的EGFR突变和野生型肺细胞的细胞活力和凋亡被测量。通过计算机模拟和热稳定性测定评估了AICAR结合蛋白。蛋白质-蛋白质相互作用通过双重免疫荧光染色和邻近连接测定可视化。通过RNA测序确定了AICAR诱导的完整转录组谱。EGFR-TL转基因小鼠肺组织被分析了MUC1表达。来自患者和转基因小鼠的器官样本和肿瘤用AICAR单独或与JAK和EGFR抑制剂联合治疗以评估治疗效果。AICAR通过诱导DNA损伤和凋亡减少了EGFR突变肿瘤细胞的生长。MUC1是AICAR结合和降解的主导蛋白之一。AICAR负调节JAK信号和JAK1-MUC1-CT相互作用。活化的EGFR增加了EGFR-TL诱导的肺癌组织中MUC1-CT的表达。AICAR减少了EGFR突变细胞系衍生的肿瘤形成。将患者和转基因小鼠肺组织衍生的肿瘤器官样本与AICAR和JAK1和EGFR抑制剂联合治疗可减少它们的生长。AICAR抑制了EGFR突变肺癌中MUC1的活性，破坏了MUC1-CT和JAK1和EGFR之间的蛋白质相互作用。 © 2023年作者。

Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate.Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects.AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth.AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR.© 2023. The Author(s).