Gut and Skin Microbiota, m6A Modification and Cell-Restricted Ferroptosis as Causal Pathways to Chronic Respiratory Diseases

To investigate how gut and skin microbiota, m6A modifications, and ferroptosis collectively influence CRDs, we utilized summary-level data from large-scale genome-wide association studies (GWAS). We assessed five CRDs: chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumoconiosis, and pulmonary arterial hypertension (PAH). Using Mendelian randomization (MR) methods, we evaluated causal relationships between these factors. Furthermore, we explored the potential mediating effects of microbiota on the m6A-CRDs axis and of ferroptosis on the microbiota-CRDs axis. To identify genes underlying these molecular layers, we confirmed significant differential expression of m6A and ferroptosis related candidates between disease and control tissues, then applied immune single-cell eQTL data across 14 distinct cell types to dissect how these genes modulate disease risk within individual immune compartments.