Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease characterized by excessive extracellular matrix accumulation, disrupted lung architecture, and declining pulmonary function, often exacerbated by severe comorbidities. To address this biological complexity, a comprehensive molecular systems architecture was developed to enable a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment. A systematic literature search was conducted across PubMed, Medline, and Google Scholar for peer-reviewed articles published from April 2008 to June 2025 using specific Medical Subject Headings (MeSH) keywords. Using the systems biology tool CytoSolve®, full-length articles were curated to construct a multi-layered framework that maps out the intricate cellular and molecular pathogenesis of the disease.


The resulting architecture integrates complex interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. External and physiological triggers—such as bleomycin, asbestos, silica, radiation, cigarette smoke, Herpes virus, genetic mutations SFTPC^I173T, and comorbidity-associated hypoxia—initiate coordinated cellular responses. These pathways ultimately converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling, which collectively drive IPF progression. Ultimately, this unified framework links triggers, cellular components, and intra- and inter-cellular molecular pathways to their pathological outcomes. By establishing this systemic foundation, the architecture serves as a critical tool for identifying novel therapeutic targets, discovering biomarkers, and designing rational single- and combination-treatment strategies to significantly enhance clinical outcomes for IPF patients.