Host m⁶A modifications shape microbiota that drives cell specific ferroptosis as a causal pathway to chronic respiratory diseases

Globally, chronic respiratory diseases (CRDs) are leading causes of mortality, morbidity, and disability-adjusted life years (DALYs), imposing substantial economic and societal burdens. Uncovering the pathogenic mechanisms underlying CRDs is therefore crucial. While prior studies have implicated gut and skin microbiota in CRD development, the extent of their influence remains inconsistent. The exact causal links between these microbial communities and CRDs are yet to be fully elucidated, and the roles of N6-methyladenosine (m⁶A) modifications and ferroptosis in these links remain poorly understood. To investigate how gut and skin microbiota, m⁶A modifications, and ferroptosis collectively influence CRDs, we used summary-level data from genome-wide association studies (GWAS). We studied five CRDs: chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumoconiosis, and pulmonary arterial hypertension (PAH). Using Mendelian randomization (MR) methods, we examined causal relationships between these factors. Furthermore, we explored the potential mediating effects of microbiota in the m⁶A-CRDs pathway and of ferroptosis in the microbiota-CRDs pathway. 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 from 14 distinct cell types to dissect how these genes modulate disease risk in individual immune cells. Our comprehensive analysis showed associations between gut and skin microbiota and CRDs. Importantly, we identified that METTL14-mediated m⁶A modification influences ILD through the gut microbiota, and that NDRG1-mediated ferroptosis plays a significant role in the progression from gut microbiota dysbiosis to COPD. Both genes were differentially expressed between disease and control tissues, and single-cell eQTL mapping localized NDRG1 exclusively to Monocyte FCGR3A + cells. Our findings provide preliminary genetic evidence of potential causal links between gut and skin microbiota and CRDs, with m⁶A modifications and cell-type-specific ferroptosis contributing to regulatory mechanisms in these pathways.