Eupalinolide A (EA) inhibits cancer progression and induces ferroptosis and apoptosis by targeting AMPK/mTOR/SCD1 signal in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a prevalent malignant neoplasm, yet the efficacy of established therapies is limited, the prognosis is poor and often comes with a high financial burden. Thus, the quest for novel drugs holds significant clinical relevance. Eupatorium lindleyanum DC. which has the main component as Eupalinolide A (EA), is clinically utilized for the management of chronic tracheitis. In our study, we aimed to investigate the effects of EA on lung cancer and to elucidate its underlying molecular mechanisms. The effects of EA on A549 and H1299 cell proliferation, migration, apoptosis were investigated by using flow cytometry, qRT-PCR, western blotting, Tunel assay, Molecular docking, RNA sequencing, Non-target Metabolomics Experimental Methodology, and Phosphoproteomics to determine the pathways and molecular targets involved. tumor growth in a xenograft model derived from human NSCLC cells were used to evaluate the anti-tumor effects of EA in vivo. EA possessed good anti-neoplastic properties in NSCLC. The anti-proliferative mechanism of EA involved the arrest of the cell cycle at the G2/M phase, the induction of apoptosis, and the promotion of ferroptosis in NSCLC. This mechanism was mediated by modulating the synthesis of unsaturated fatty acids through the downregulation of SCD1 expression. Notably, the supplementation of oleic acid can counteract EA's inhibitory effects on cell proliferation and migration. Furthermore, the AMPK- mTOR signaling pathway was implicated in EA's function within NSCLC.In conclusion, our study demonstrated that EA can inhibit the proliferation and migration of lung cancer cells by modulating the lipid metabolism through activating the ROS-AMPK-mTOR-SCD1 signaling pathway. EA emerges as a promising candidate for the development of therapeutics against non-small cell lung cancer.