获得性EGFR-TKI治疗耐药的发展仍然是非小细胞肺癌（NSCLC）治疗的主要临床挑战。本研究旨在探讨HDAC1/FOXK1/miR-33a信号在EGFR-TKI耐药中的作用。利用定量聚合酶链反应（PCR）和生物信息学分析检测miR-33a、HDAC1和FOXK1的表达水平。分别通过细胞数测定、Transwell 和流式细胞术测定来探索细胞增殖、迁移和凋亡。细胞中过表达或敲低HDAC1、miR-33a表达后，检测细胞功能。使用免疫沉淀和相关分析来评估 HDAC1 和 FOXK1 蛋白之间的相互作用。通过动物实验研究了miR-33a的肿瘤抑制作用。miR-33a的抑制通过影响吉非替尼耐药细胞的增殖、迁移和凋亡来增加TKI耐药性。 HDAC1是抑制miR-33表达的关键上游分子。 HDAC1 上调通过与细胞中的 FOXK1 结合来沉默 miR-33a 表达，从而增加吉非替尼耐药性。 MiR-33a 过表达通过负调节 ABCB7 和 p70S6K1 表达发挥肿瘤抑制作用。此外，miR-33a 的过表达可抑制异种移植裸鼠模型中的肿瘤生长。HDAC1/FOXK1 上调和 miR-33a 沉默是 NSCLC EGFR-TKI 耐药的新机制。© 2024。作者。

The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance.The expression levels of miR-33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments.The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model.HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC.© 2024. The Author(s).