Related Experiment Video
Updated: Jun 18, 2026
Assessment of Mitochondrial Health in Cancer-Associated Fibroblasts Isolated from 3D Multicellular Lung Tumor Spheroids
Published on: October 21, 2022
An integrative framework combining Mendelian randomization, single-cell profiling, and experimental validation
Shouyong Xiao1, Siyun Wu2, Xianfeng Shao1
1Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University / Yunnan Cancer Hospital / Peking University Cancer Hospital Yunnan , Kunming, 650118, Yunnan, China.
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).
