OBJECTIVE: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Herein, we probed into the role of E3 ubiquitin protein ligase family member 1 (HERC1) in promoting ferroptosis and inhibiting LUAD cell proliferation by regulating RAF proto-oncogene serine/threonine-protein kinase (C-RAF). METHODS: In cultured human normal lung epithelial cells and non-small cell lung adenocarcinoma cell lines, HERC1 expression was determined by RT-qPCR and Western blot tests. PC-9 and Calu-3 cells were transfected with oe-HERC1, oe-C-RAF or their negative controls. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and Fe RESULTS: HERC1 was poorly expressed in LUAD cells. HERC1 promoted LUAD cell ferroptosis and repressed their proliferation and migration, corresponding to reduced levels of system xc-, GPX4, and GSH, as well as elevated levels of ROS, MDA, Fe CONCLUSION: HERC1 expedites C-RAF ubiquitin degradation by interacting with C-RAF, which consequently promotes ferroptosis, thereby inhibiting LUAD cell proliferation.