From Adipose Tissue to Alveoli: Bioinformatic Mapping of Obesity-Associated Lung Injury Pathways

Introduction: Obesity represents a systemic inflammatory state predisposing individuals to enhanced acute respiratory distress syndrome susceptibility, yet molecular mechanisms linking adipose tissue dysfunction to lung injury remain poorly characterized. Objective: To establish a bioinformatics framework mapping molecular pathways connecting obesity-associated adipose tissue dysfunction to lung injury susceptibility through cross-tissue transcriptomic analysis. Methods: We analyzed publicly available 23 high-quality datasets from GEO database comprising 1,247 adipose tissue samples (683 obese, 564 lean) and 834 lung samples (445 ARDS patients, 389 controls). Differential expression analysis employed limma-voom and DESeq2 frameworks with study-specific blocking factors. Gene Set Enrichment Analysis utilized human-specific databases with significance thresholds of FDR q<0.25 and |NES|>1.0. Protein-protein interaction networks were constructed using STRING database with confidence scores >0.7. Statistical analyses included hypergeometric tests for pathway overlap, meta-analysis with random-effects models, and logistic regression for clinical correlations. External validation employed three independent cohorts with forest plot analysis and Egger's regression for publication bias assessment. Results: Analysis identified 2,847 dysregulated genes in obese adipose tissue and 1,892 in lung injury samples, with 347 genes commonly altered (p<0.001). Key hub genes included IL6, TNF, STAT3, and NFKB1, orchestrating inflammatory cascades. Cross-tissue analysis revealed 43 shared pathways, predominantly TNF-NF-κB signaling (NES=2.84) and IL6-STAT3 pathways (NES=2.63). The inflammatory pathway score correlated with mechanical ventilation duration (r=0.67, p<0.001) and predicted 30-day mortality (OR=2.34, 95% CI: 1.45-3.78). Conclusion: Our results demonstrated that obesity-induced adipose inflammation promotes lung injury susceptibility through TNF-NF-κB and IL6-STAT3 pathway activation, revealing therapeutic targets for respiratory complications.