Zeng Yingou, Wang Qiang, Qiao Di, Dai Bin, Wu Yunlong, Wang Meng, Fan Zhe, Chen Jia
Department of Cardiothoracic Surgery, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
Department 2 of Thoracic Surgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
BMC Cancer. 2025 Aug 18;25(1):1335. doi: 10.1186/s12885-025-14729-1.
Non-small-cell lung cancer (NSCLC) is a highly aggressive cancer with a poor prognosis, largely due to increasing resistance to Tyrosine Kinase Inhibitors (TKIs). The mechanisms of NSCLC TKI resistance remain unknown. This study aimed to elucidate the molecular mechanism of METTL16-mediated GPX4 mA modification and its underlying function in regulating the proliferation and AZD-9291 resistance of NSCLC.
TCGA, and GEO datasets were used to analyze the differential expression of mA-modified GPX4 in NSCLC and adjacent tissues, and its impact on prognosis. Then the GPX4 induced ferroptosis escape promoted the proliferation and AZD-9291 resistance of PC9 and HCC827 cells. The regulatory mechanism of METTL16/GPX4 and its interaction in cancer progression were investigated through MeRIP, Western blots, dual-luciferase reporter assay, and rescue experiments.
METTL16 was significantly upregulated in NSCLC tissue and was associated with a worse prognosis. Overexpression of METTL16 significantly promoted the proliferation and AZD-9291 resistance of NSCLC, while METTL16 knockdown inhibited the above phenotype. Through bioinformatic analysis and experimental results, we found that GPX4 mRNA is a substrate of METTL16. GPX4 was upregulated in AZD-9291-resistant NSCLC cells and ferroptosis was inhibited. As a key regulator of ferroptosis, METTL16 mediated GPX4 mA modification promoted NSCLC proliferation and AZD-9291 resistance through inhibiting ferroptosis. Further, targeting METTL16 exhibited pro-ferroptosis function and AZD-9291 sensitivity of NSCLC.
In summary, we found that METTL16-mediated GPX4 modification promoted the proliferation and AZD-9291 resistance of NSLCL by inhibiting ferroptosis activity. Our study is expected to provide a novel insight and potential therapeutic target for NSCLC AZD-9291 resistance.
非小细胞肺癌（NSCLC）是一种侵袭性很强且预后较差的癌症，这主要归因于对酪氨酸激酶抑制剂（TKIs）的耐药性不断增加。NSCLC对TKI产生耐药性的机制尚不清楚。本研究旨在阐明METTL16介导的GPX4 mA修饰的分子机制及其在调节NSCLC增殖和对AZD-9291耐药性中的潜在作用。
利用TCGA和GEO数据集分析NSCLC组织和癌旁组织中mA修饰的GPX4的差异表达及其对预后的影响。然后，GPX4诱导的铁死亡逃逸促进了PC9和HCC827细胞的增殖及对AZD-9291的耐药性。通过MeRIP、蛋白质免疫印迹、双荧光素酶报告基因检测和拯救实验研究了METTL16/GPX4的调控机制及其在癌症进展中的相互作用。
METTL16在NSCLC组织中显著上调，且与较差的预后相关。METTL16的过表达显著促进了NSCLC的增殖及对AZD-9291的耐药性，而敲低METTL16则抑制了上述表型。通过生物信息学分析和实验结果，我们发现GPX4 mRNA是METTL16的底物。GPX4在对AZD-9291耐药的NSCLC细胞中上调，铁死亡受到抑制。作为铁死亡的关键调节因子，METTL16介导的GPX4 mA修饰通过抑制铁死亡促进了NSCLC的增殖及对AZD-9291的耐药性。此外，靶向METTL16表现出促进NSCLC铁死亡的作用及对AZD-9291的敏感性。
总之，我们发现METTL16介导的GPX4修饰通过抑制铁死亡活性促进了NSLCL的增殖及对AZD-9291的耐药性。我们的研究有望为NSCLC对AZD-9291的耐药性提供新的见解和潜在的治疗靶点。
