Abstract
BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality globally, necessitating finding novel therapeutic targets. Mitochondrial autophagy (mitophagy) and ferroptosis have emerged as promising avenues in cancer research. This study aimed to identify mitophagy- and ferroptosis-related genes (MiFeRGs) in LUAD and develop a prognostic risk model based on these genes. METHODS: Integration of transcriptomic data from the TCGA dataset with MiFeRG databases was performed. Subsequently, differentially expressed MiFeRGs were identified. A prognostic risk model was developed using univariate, LASSO, and multivariate Cox regression analyses. Survival analysis, immune infiltration assessment, and GSEA analysis were conducted to evaluate the prognostic value and potential mechanisms of MiFeRGs in LUAD. Expression levels and functions of prognostic MiFeRGs were further validated in cells. RESULTS: A total of 136 differentially expressed MiFeRGs were identified, with enrichment in signaling pathways associated with cancer progression. Seven MiFeRGs (ARPC1A, AURKA, BRD2, HNRNPL, METTL3, NR4A1, and TRPM2) were selected for the prognostic risk model. The model showed wide applicability across various clinical parameters. Furthermore, the PPI network revealed potential associations between MiFeRGs and TCR-related genes, with hub MiFeRG AURKA and TCR-related gene AKT1 having the highest degree values. The levels of AURKA were upregulated in the LUAD cell line and tumor tissues. Moreover, AURKA was associated with mTORC1 activation. CONCLUSION: The identified MiFeRGs and the developed prognostic risk model provide valuable insights into the molecular mechanisms underlying LUAD progression and offer potential prognostic and therapeutic implications for clinical management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-025-02216-2.