Pulmonary Fibrosis Beyond the Lung: Adipose Tissue as a Systemic Modifier of Fibrotic Remodeling

Pulmonary fibrosis is increasingly viewed as a lung-centered disease influenced by systemic metabolic and inflammatory context. Adipose tissue, through its endocrine, paracrine, and immunometabolic functions, may act as a systemic modifier rather than a primary initiator of fibrotic remodeling. Epidemiologic and imaging studies link visceral adiposity, body composition, and adipose-related mediators such as leptin and IL-6 with subclinical interstitial abnormalities and outcomes in fibrotic ILD, while genetic and clinical data support a context-dependent protective role for adiponectin signaling. Mechanistic evidence suggests that adipose dysfunction may influence fibrotic remodeling through adipokine imbalance, inflammasome activation, perivascular inflammation, profibrotic macrophage polarization, epithelial maladaptation, cellular senescence, and fibroblast metabolic reprogramming. These pathways may converge to sustain myofibroblast activation and extracellular matrix deposition. Clinically, adipose dysfunction overlaps with common ILD comorbidities and may inform metabolic phenotyping, biomarker development, and patient stratification. Therapeutic implications remain investigational, with the strongest rationale supporting metabolic reprogramming strategies and biomarker-enriched studies rather than routine adipose-targeted therapy. Overall, the adipose–lung axis provides a framework for integrating systemic metabolic biology into the pathogenesis and clinical management of fibrotic ILD.