ATF4/SCO2 Inhibits Ferroptosis in Lung Cancer Through Activating the MAPK Signaling Pathway

ABSTRACT

Ferroptosis is a specific cell death form resulting from the iron‐dependent lipid peroxidation, exhibiting an essential role in cancer progression. The purpose of this study was to explore the underlying mechanism of ferroptosis in lung cancer. The mRNA and protein expression levels were examined via real‐time quantitative PCR and Western blotting. Cell malignant behaviors were assessed using cell counting kit‐8 (CCK‐8) assay, transwell assay, and flow cytometry. Ferroptosis was determined using the indicators lipid reactive oxygen species (ROS), glutathione (GSH), and Fe ²⁺ . Dual‐luciferase reporter assay and chromatin immunoprecipitation assay were performed for binding analysis between activating transcription factor 4 (ATF4) and synthesis of cytochrome c oxidase 2 (SCO2). Associated proteins in mitogen‐activated protein kinases (MAPK) signaling pathway were measured by Western blotting. A mouse model was established by implanting lung cancer cells for in vivo research. Lung cancer samples and cells exhibited high expression of SCO2. SCO2 downregulation restrained lung cancer cell growth by inducing ferroptosis. ATF4 was an up‐regulated gene in lung cancer, and it elevated SCO2 expression by binding to the promoter of SCO2. ATF4 knockdown repressed cell proliferation and migration while facilitating apoptosis and ferroptosis by down‐regulating SCO2. Inhibition of ATF4/SCO2 inactivated the MAPK signaling pathway. ATF4‐mediated SCO2 promoted lung tumorigenesis in vivo. This study manifested that ATF4 controlled SCO2 to suppress ferroptosis by activating the MAPK pathway, thus contributing to lung cancer development.