Artesunate reverses gefitinib resistance in lung adenocarcinoma by inducing ferroptosis and suppressing the Wnt/β-catenin pathway
- Eur J Pharmacol. 2026 Apr 28:1022:178856. doi: 10.1016/j.ejphar.2026.178856.
- 1. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350102, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350102, China.
- 2. Department of Clinical Laboratory, Xiapu County Hospital of Fujian Province, Ningde, 355100, China.
- 3. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350102, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou, 350102, China.
- 4. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350102, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou, 350102, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: [email protected].
- 5. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350102, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350102, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou, 350102, China; Central Laboratory, Fujian Provincial Hospital, Fuzhou, 350102, China; Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Key Laboratory of Cardiovascular Disease, Fuzhou, 350102, China. Electronic address: [email protected].
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve survival outcomes in lung adenocarcinoma (LUAD) patients, resistance inevitably remains a critical therapeutic challenge. Artesunate (ART) has demonstrated antitumor potential in various malignancies, but whether ART increases the efficacy of EGFR-TKIs and reverses drug resistance in LUAD remains unexplored. In this research, the reversal effects and potential mechanisms of ART in gefitinib-resistant LUAD were investigated both in vitro and in vivo. ART effectively suppressed the viability, migration, invasion and colony formation of gefitinib-resistant cells. ART induced Ferroptosis in LUAD by promoting Fe2+ accumulation, ROS formation, and MDA production and suppressing the GSH/GSSG ratio as well as the ferroptosis-related proteins SLC7A11 and GPX4. Mechanistically, ART was found to inhibit the Wnt/β-catenin pathway by upregulating GSK3β and p-β-catenin expression while downregulating β-catenin, TCF4, Cyclin D1 and c-Myc expression, thereby promoting Ferroptosis. These finding revealed that ART is an effective Anticancer drug that enhances the therapeutic efficacy of gefitinib in LUAD cells by inducing Ferroptosis and suppressing the Wnt/β-catenin pathway, which provides a promising foundation for the combined application of ART and EGFR-TKIs in the treatment of LUAD.