〔Abstract〕 Objective To investigate the effect of human angiopoietin-like protein 4(ANGPTL4) on the invasion and migration of gefitinib-resistant lung adenocarcinoma strains and its mechanism. Methods The expression of ANGPTL4 in PC9/GR cells was interfered by siRNA method, and the interference effect was verified by Western blot and qRT-PCR. The CCK-8 experiment was performed to verify the inhibitory effect of interfering with ANGPTL4 on the proliferation of PC9/GR cells. The scratch experiment and transwell experiment were performed to detect the invasion and metastasis ability of cells; the expression levels of Vimentin, E-cadherin and N-cadherin were detected by Western blot experiment. Results The expression of ANGPTL4 in PC9/GR cells was significantly higher than that in PC9 cells. The CCK-8 experiment proved that the IC50of PC9/GR cells to gefitinib was higher than that of PC9 cells, and the IC50was significantly reduced after interfering with the expression of ANGPTL4 in PC9/GR cells; scratch experiment and Transwell migration experiment showed that after interfering with the expression of ANGPTL4 in PC9/GR cells, the wound healing ability, migration and invasion ability of the cells were significantly reduced. The results of Western blot experiments showed that the expression of N-cadherin and Vimentin decreased and the expression of E-cadherin increased in PC9/GR cells after interference. Conclusion ANGPTL4 may participate in the acquired drug resistance of gefitinib in lung adenocarcinoma, and promote the invasion and metastasis of PC9/GR cells. Interference with ANGPTL4 can inhibit the EMT process of PC9/GR cells.