Molecular Convergence Between Idiopathic Pulmonary Fibrosis and Its Comorbidities Reveals Interactions Between Pulmonary and Systemic Regulatory Programs

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by high mortality and marked clinical heterogeneity. A defining yet insufficiently understood feature of IPF is its frequent coexistence with pulmonary and extrapulmonary comorbidities. However, the molecular basis that underlies this multisystem involvement remains unclear. We applied an integrative systems-level framework that combines lung-derived transcriptomic datasets with curated disease–gene associations across major IPF-associated comorbidities. Network organization and functional stratification analyses were used to characterize shared and disease-specific molecular modules, and independent transcriptomic datasets were analyzed to evaluate the consistency of these patterns. These analyses revealed structured molecular convergence between IPF and its comorbidities organized into two interacting biological programs: a lung-enriched fibrotic–mechanical program and a systemically distributed neuroimmune–metabolic program. These programs are interconnected through a shared regulatory interface that includes IL6, AKT1, TGFB1 and STAT3. This organization was consistently observed across independent datasets. IPF emerges from the interaction between pulmonary and systemic regulatory programs rather than isolated lung-restricted mechanisms. This framework provides a basis for understanding disease heterogeneity and comorbidity burden, with potential implications for stratification and therapeutic targeting.