{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:02:48Z","timestamp":1785322968088,"version":"3.55.0"},"reference-count":170,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial lung disease characterized by excessive extracellular matrix (ECM) accumulation, disruption of lung architecture, and progressive loss of pulmonary function. IPF is frequently accompanied by comorbid conditions that exacerbate disease progression and negatively impact prognosis. To address the biological complexity of IPF, this study presents a comprehensive molecular systems architecture that enables a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment in response to external and physiological triggers. Methods: A literature search is conducted using the Medical Subject Headings (MeSH) keywords in PubMed and MEDLINE to identify relevant peer-reviewed articles published from April 2008 to June 2025, with Google Scholar used solely to retrieve full-text versions of articles identified through this search. The systems biology tool CytoSolve\u00ae was used to perform the systematic review and to support the curation and development of the molecular systems architecture of IPF pathogenesis. Full-length articles that contained Medical Subject Headings keywords relevant to IPF pathogenesis were selected for a comprehensive review. A total of 150 studies published between April 2008 and June 2025 met the inclusion criteria and were included in the systematic analysis. This systematic review was not registered. Results: Findings were synthesized qualitatively into a multilayered molecular interactome rather than through statistical meta-analysis. The architecture integrates interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. Key external triggers\u2014such as bleomycin (BLM), asbestos, silica, radiation, cigarette smoke, Herpes virus, and genetic mutations (SFTPC I73T), along with hypoxia associated with comorbidities\u2014initiate coordinated cellular responses that converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling. These interconnected processes collectively drive the initiation and progression of IPF. Conclusions: This molecular systems architecture unifies triggers, cellular components, molecular pathways, and biological processes into a multilayered framework for identifying therapeutic targets, biomarkers, and rational single- and combination-treatment strategies in IPF.<\/jats:p>","DOI":"10.3390\/cells15151364","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"1364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Systems Architecture of Fibrotic Lung Microenvironment in Idiopathic Pulmonary Fibrosis"],"prefix":"10.3390","volume":"15","author":[{"given":"V. A. Shiva","family":"Ayyadurai","sequence":"first","affiliation":[{"name":"Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA 02138, USA"},{"name":"The Open Science Institute, International Center for Integrative Systems, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamuna","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA 02138, USA"},{"name":"The Open Science Institute, International Center for Integrative Systems, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhakar","family":"Deonikar","sequence":"additional","affiliation":[{"name":"Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA 02138, USA"},{"name":"The Open Science Institute, International Center for Integrative Systems, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s00109-021-02113-y","article-title":"The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis","volume":"99","author":"Bolourani","year":"2021","journal-title":"J. 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