We observed increased APT1 in osimertinib-resistant cells, and further exploration revealed that APT1 could promote osimertinib resistance by depalmitoylating MST1 and enhancing YAP1 nuclear translocation, revealing a novel mechanism by which APT1 regulates osimertinib resistance in NSCLC through depalmitoylation. This evidence concerns the gene LYPLA1 and non-small cell lung carcinoma.