An integrative framework combining Mendelian randomization, single-cell profiling, and experimental validation identifies FTMT as a mitochondrial–immune regulator in non-small cell lung cancer

Background Mitochondrial iron handling and immune surveillance are intertwined in tumor biology. Mitochondrial ferritin (FTMT) buffers redox-active iron in mitochondria, while MICB is an NKG2D ligand that can promote anti-tumor cytotoxicity when expressed on tumor cells. However, whether FTMT has a causal relationship with non-small cell lung cancer (NSCLC) risk—and how this might connect to MICB biology—remains uncertain. Methods We applied a genetics–omics–validation workflow. We conducted two-sample Mendelian randomization (MR) and mediation MR using plasma proteomic pQTL summary statistics (UK Biobank Pharma Proteomics Project) and NSCLC GWAS summary statistics from FinnGen (R12). To contextualize results in the tumor microenvironment, we interrogated single-cell RNA-seq datasets via TISCH2 and explored pharmacogenomic associations using GDSC. Mechanistic plausibility was tested in A549 lung adenocarcinoma cells using FTMT overexpression followed by qPCR and Western blotting. Results Genetically predicted higher FTMT levels were associated with reduced NSCLC risk (IVW OR per 1-SD increase ≈ 0.91). Mediation MR suggested that MICB-related signals accounted for a modest proportion of the FTMT effect. Single-cell analyses showed FTMT enrichment in malignant epithelial cells, whereas MICB was expressed across multiple compartments. In vitro, FTMT overexpression increased MICB mRNA and protein abundance. Conclusions Integrating genetic evidence, tumor-context transcriptomics, and cell-based validation supports FTMT as a protective factor for NSCLC and points to a mitochondrial–immune axis involving MICB. Observed differences between blood-based genetic proxies and tumor-cell experiments are consistent with context-dependent regulation (e.g., circulating MICB can reflect shedding, whereas tumor-cell MICB reflects surface stress-ligand programs).