{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:37:57Z","timestamp":1790095077485,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The therapeutic strategy for Idiopathic Pulmonary Fibrosis (IPF) has undergone a fundamental transformation over recent decades. Combination therapy with glucocorticoids and immunosuppressants, particularly the \u201ctriple therapy\u201d regimen including corticosteroids, azathioprine, and an antioxidant, has shifted from being the standard of care to being completely abandoned. This article reviews the key evidence-based milestones in this historical shift and, grounded in a modern understanding of the disease\u2019s nature, delves into the pathophysiological basis for the ineffectiveness and even harm of glucocorticoids and immunosuppressants in IPF. The core argument posits that IPF is a disorder of immune microenvironment dysregulation, initiated by persistent alveolar epithelial injury, driven by pro-fibrotic phenotype macrophages, and ultimately resulting in myofibroblast activation and aberrant extracellular matrix deposition. Traditional glucocorticoids and immunosuppressants, whose primary target cells are lymphocytes, are misaligned with the core immune drivers (macrophages) and effector cells (myofibroblasts) of IPF. Consequently, they not only fail to reverse the fibrotic process but may also potentially promote fibrogenesis by enhancing transforming growth factor-beta (TGF-\u03b2) signaling pathways, inducing factors like CTGF, and they carry significant safety risks. Current treatment for IPF has fully transitioned into an era centered on antifibrotic therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1830573","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:39:43Z","timestamp":1779169183000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The rise and fall of glucocorticoids and immunosuppressants in idiopathic pulmonary fibrosis: a historical paradigm shift driven by mechanistic understanding"],"prefix":"10.3389","volume":"17","author":[{"given":"Bing","family":"Wen","sequence":"first","affiliation":[{"name":"The First Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Department of Geriatrics, Taiyuan Second People's Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wu","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Department of Respiratory and Critical Care Medicine, Taiyuan Central Hospital, The Ninth Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosheng","family":"Ma","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"The First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Qian","sequence":"additional","affiliation":[{"name":"The First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01130-2018","article-title":"SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772)","volume":"52","author":"Raghu","year":"2018","journal-title":"Eur Respir J"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.2.ats3-00","article-title":"Idiopathic pulmonary fibrosis: diagnosis and treatment. 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