HHLA3 Silencing Suppresses KRAS‐Mutant Non‐Small‐Cell Lung Cancer Cell Progression Through Triggering MYEOV‐Mediated Ferroptosis

ABSTRACT KRAS mutation is one of the most common mutational events in non‐small‐cell lung cancer (NSCLC). However, due to the complex signaling pathways and high biological heterogeneity of KRAS‐mutant NSCLC, the current clinical treatment for patients with KRAS mutations still faces many difficulties. The oncogenic effector in KRAS‐mutant NSCLC was screened using GEO data sets. CCK‐8, colony formation, transwell, and flow cytometry were conducted to assess the malignant phenotype of KRAS‐mutant NSCLC cells. The indicators intracellular Fe 2+ , ROS, GSH, and MDA levels were employed to reflect the ferroptosis of cells. The mechanism of myeloma overexpressed (MYEOV) in KRAS‐mutant NSCLC was explored from the perspective of noncoding RNA (ncRNA) and validated by rescue experiments. MYEOV presented a high expression trend in KRAS‐mutant NSCLC specimens. MYEOV silencing effectively repressed the malignant phenotype and promoted ferroptosis of NSCLC cells carrying KRAS mutations. Based on bioinformation analysis and a series of rescue experiments, we established the HHLA3/miR‐139‐5p/MYEOV regulatory network in KRAS‐mutant NSCLC cells and disclosed that HHLA3 served as a molecular sponge for miR‐139‐5p to regulate MYEOV expression. The mechanism of MYEOV and its ncRNA network affecting the progression of KRAS‐mutant NSCLC revealed in this study intends to provide a theoretical basis for KRAS‐mutant NSCLC treatment.