Investigating the role of TIMM8B in lung adenocarcinoma: Expression patterns, prognostic value, and therapeutic implications

Introduction: Translocase of inner mitochondrial membrane 8 homolog B (TIMM8B) is crucial for mitochondrial function, but its role in lung adenocarcinoma (LUAD) remains underexplored. Objective: This study investigates TIMM8B expression patterns, prognostic value, and potential therapeutic implications in LUAD. Methods: The expression and prognostic potential of TIMM8B in LUAD were analyzed using data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression, Gene Expression Omnibus, and Gene Expression Profiling Interactive Analysis 2, with survival analysis performed through Kaplan–Meier plotter. The prognostic value was validated using a LUAD tissue microarray and a nomogram. TIMM8B-related differentially expressed genes were identified using TCGA and LinkedOmics, and were functionally annotated using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Immunological features were assessed using TCGA data through the XCELL and tumor immune dysfunction and exclusion algorithms. Associations among TIMM8B, m6A modification, ferroptosis-related genes, and tumor genetic mutations were analyzed using TCGA data. Drug response correlations were explored using the Genomics of Drug Sensitivity in Cancer and Comparative Toxicogenomics databases. TIMM8B-depleted LUAD cell lines were analyzed using ribonucleic acid sequencing and subjected to cell cycle analysis. Results: TIMM8B is overexpressed in multiple cancers, including LUAD. High TIMM8B expression correlates with poorer overall survival in LUAD. A nomogram incorporating TIMM8B and pathological tumor-node-metastasis stage showed reliable predictive performance. TIMM8B-related gene analyses suggest roles in cell adhesion, chromosome segregation, and critical cancer pathways. TIMM8B shapes an immunosuppressive tumor microenvironment in LUAD, affecting immune cell infiltration and immunotherapy response. Elevated TIMM8B expression is associated with TP53 mutations and chemotherapy resistance. Knockdown of TIMM8B in H1299 cells downregulates PD-L1, induces G1 phase arrest, and triggers a chemokine (C-C motif) ligand 2-mediated inflammatory response, highlighting roles in cell cycle regulation and inflammatory pathways. Conclusion: These findings underscore TIMM8B’s multifaceted role in cancer progression and its potential as a prognostic marker and therapeutic target in LUAD.