Harringtonine Elicits Ferroptosis by Regulating SYVN1 ‐Mediated FASN Ubiquitination for Evoking Anti‐Lung Cancer Efficacy

ABSTRACT Harringtonine (HT) is an alkaloid extracted from the botanical cephalotaxus fortunei Hook.f ., which has potent anti‐tumor activity. Nevertheless, the target and mechanism of HT in cancer have not been reported. The present work aims to explore the crucial target of HT in triggering ferroptosis and elucidate its mechanism. Lewis lung cancer cells and tumor‐bearing mice models prepared thereof were used in this study. Network pharmacology and RNA sequencing were utilized to screen the pivotal target and information. Flow cytometry, Western blots, qRT‐PCR, and immunoprecipitation were exploited to elucidate the mechanism. The affinity experiments were employed to analyze the interaction of HT and FASN. Reduced cell viability and increased apoptosis were observed in HT‐treated lung cancer cells and the 3‐D cell model. Consistently, HT exhibited pronounced anti‐cancer effects in in vivo experiments. The interaction molecules of HT and lung cancer were enriched in ferroptosis, which was validated by the accumulation of ferrous ions etc. Blockage of ferroptosis mitigated HT‐mediated efficacy. Further investigation showed alternations in fatty acid metabolism when adding HT, especially fatty acid synthase (FASN). HT was demonstrated to bind to FASN, thereby dampening SYVN1‐mediated ubiquitination. Finally, the silence of FASN dampened the ferroptosis and anti‐cancer efficacy introduced by HT. Collectively, HT could bind to FASN and thereby enhance the activity by reducing ubiquitination, resulting in increased fatty acid synthesis and infiltrating into the membrane, which leads to ferroptosis. The present work identifies the critical target for phytomedicine HT‐driven ferroptosis and provides a foundation for cancer therapy.