COPZ1 regulates ferroptosis through NCOA4-mediated ferritinophagy in lung adenocarcinoma

Abstract Background Ferroptosis, a type of autophagy-dependent cell death, is intricately related to the pathogenesis of lung adenocarcinoma (LUAD). The research focus of this study was to investigate the involvement of coatomer protein complex I subunit zeta 1 (COPZ1) in ferroptosis and ferritinophagy in LUAD. Methods In this study, clinical samples of LUAD and para-carcinoma tissues were gathered. Lentiviral vectors were utilized to establish COPZ1-deficient LUAD cell model and xenograft model. These models were analyzed to assess tumor growth, lipid peroxidation levels, autophagy activation, and iron metabolism. To demonstrate the regulatory effects of COPZ1 on its downstream targets, qRT-PCR, Western blot, and co-immunoprecipitation (co-IP) assay were conducted. Moreover, NCOA4 knockdown plasmid was applied. The location of ferritin and lysosomes were examined using immunofluorescence staining. Results The study revealed that LUAD tissues and cells exhibited elevated expression of COPZ1. COPZ1 silencing inhibited xenograft tumor growth and induced apoptosis. COPZ1 silencing also promoted the accumulation of ROS, Fe2+, MDA and 4-HNE while reducing GSH-Px levels. In addition, COPZ1 was found to directly bind to nuclear receptor coactivator 4 (NCOA4). COPZ1 silencing inhibit the expression of FTH1 and promoted the expression of NCOA4 and LC3. NCOA4 knockdown reversed the iron metabolism and lipid peroxidation regulation induced by COPZ1 silencing. Furthermore, COPZ1 silencing induced the translocation of ferritin to lysosomes for degradation, while NCOA4 knockdown disrupted this process. Conclusion This study presents novel findings showing that COPZ1 regulates NCOA4-mediated ferritinophagy and ferroptosis. These results offer new insights into the development and potential treatment of LUAD.