肺癌的病理生理学取决于凋亡和自噬途径的失衡。凋亡和自噬之间通过共享的信号通路的复杂联系，使我们对肺癌病理生理学的调控方式理解更加复杂。由于药物耐药是治疗失败的主要原因，因此了解癌细胞对不同治疗方法的反应以及如何整合凋亡和自噬之间的交互作用响应这些治疗方法，从而导致细胞死亡或存活，非常关键。因此，在这项研究中，我们试图评估A549肺癌细胞系中自噬和凋亡之间的交互作用，该细胞系可以通过联合使用抗糖尿病药物二甲双胍（6mM）和Hsp90抑制剂格杜尼（12µM）的组合治疗来调节，以洞察新癌症治疗发展的见解。我们的结果表明，二甲双胍和格杜尼对A549肺癌细胞具有细胞毒性。二甲双胍和格杜尼的组合产生ROS促进线粒体膜电位丢失和DNA损伤。组合进一步增加了AMPKα1的表达并促进了AMPKα1/α2的核定位。Hsp90的表达下调，进一步减少了其客体EGFR、PIK3CA、AKT1和AKT3的表达。EGFR/PI3K/AKT通路的抑制上调了TP53并抑制了自噬。组合物推动p53核定位，不过也检测到了一些细胞浆信号。还观察到了caspase 9和caspase 3表达的进一步增加。因此，我们得出结论，二甲双胍和格杜尼的联合通过抑制EGFR/PI3K/AKT途径和自噬，在A549肺癌细胞中上调了凋亡。© 2023年作者，独家许可Springer Science+Business Media，LLC的一部分，Springer Nature。

The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.