肺癌是最致命的恶性肿瘤，非小细胞肺癌（NSCLC）是最常见的类型（约占85%）。表皮生长因子受体（EGFR）异常激活促进了NSCLC的发展。EGFR突变引起的酪氨酸激酶抑制剂的化疗耐药性是NSCLC治疗的关键挑战。因此，需要更全面地了解EGFR表达和动力学。使用人类非小细胞肺癌细胞和HEK293FT细胞，通过Western印迹分析、免疫共沉淀和免疫荧光研究气孔素E（GSDME）调节EGFR稳定性的分子机制。使用GSDME和EGFR siRNA或过表达质粒来表征GSDME和EGFR的体外功能作用。同时使用EdU包含、CCK-8和集落形成实验来确定非小细胞肺癌细胞的增殖能力。GSDME减少导致非小细胞肺癌细胞的体外增殖。重要的是，GSDME-全长（GSDME-FL）和GSDME-N碎片都与EGFR发生物理相互作用。GSDME与EGFR的胞浆片段相互作用。GSDME敲除抑制了EGFR二聚化和酪氨酸1173（EGFRY1173）的磷酸化，激活了ERK1/2。GSDME敲除还促进了EGFR酪氨酸1045（EGFRY1045）的磷酸化和其降解。这些结果表明，GSDME-FL增加了EGFR的稳定性，而GSDME N末端片段诱导EGFR的降解。GSDME-EGFR相互作用在非小细胞肺癌的发展中起着重要作用，揭示了GSDME与EGFR稳定性之间以前未被认识的联系，为癌症发病机制提供了新的见解。视频摘要。©2023年，作者。

Lung cancer is the most lethal malignancy, with non-small cell lung cancer (NSCLC) being the most common type (~ 85%). Abnormal activation of epidermal growth factor receptor (EGFR) promotes the development of NSCLC. Chemoresistance to tyrosine kinase inhibitors, which is elicited by EGFR mutations, is a key challenge for NSCLC treatment. Therefore, more thorough understanding of EGFR expression and dynamics are needed.Human non-small cell lung cancer cells and HEK293FT cells were used to investigate the molecular mechanism of gasdermin E (GSDME) regulating EGFR stability by Western blot analysis, immunoprecipitation and immunofluorescence. GSDME and EGFR siRNAs or overexpression plasmids were used to characterize the functional role of GSDME and EGFR in vitro. EdU incorporation, CCK-8 and colony formation assays were used to determine the proliferation ability of non-small cell lung cancer cells.GSDME depletion reduced the proliferation of non-small cell lung cancer cells in vitro. Importantly, both GSDME-full length (GSDME-FL) and GSDME-N fragment physically interacted with EGFR. GSDME interacted with cytoplasmic fragment of EGFR. GSDME knockdown inhibited EGFR dimerization and phosphorylation at tyrosine 1173 (EGFRY1173), which activated ERK1/2. GSDME knockdown also promoted phosphorylation of EGFR at tyrosine 1045 (EGFRY1045) and its degradation.These results indicate that GSDME-FL increases the stability of EGFR, while the GSDME N-terminal fragment induces EGFR degradation. The GSDME-EGFR interaction plays an important role in non-small cell lung cancer development, reveal a previously unrecognized link between GSDME and EGFR stability and offer new insight into cancer pathogenesis. Video abstract.© 2023. The Author(s).