{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:32:00Z","timestamp":1786422720605,"version":"build-2736575974"},"reference-count":77,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The lack of effective anti-fibrotic agents remains a significant unmet need in the treatment of intestinal fibrosis, a condition largely driven by transforming growth factor-\u03b21 (TGF-\u03b21)-mediated myofibroblast activation. Phosphodiesterase 4 (PDE4) inhibitors, known to increase intracellular cAMP levels, exhibit anti-inflammatory and potential anti-fibrotic properties, though their efficacy in intestinal fibrosis is poorly defined. In this study, we investigated the anti-fibrotic effects and underlying mechanisms of PDE4 inhibitors (rolipram, roflumilast, piclamilast, and mesopram) in human intestinal myofibroblasts (HIMFs) stimulated with TGF-\u03b21. All PDE4 inhibitors significantly reduced TGF-\u03b21-induced mRNA expression of collagen1A1 (COL1A1) and fibronectin (FN1), with mesopram additionally reducing \u03b1-smooth muscle actin (ACTA2) mRNA expression. At the protein level, however, only roflumilast significantly decreased procollagen1A1 (Procol1A1) and FN expression. Mechanistically, roflumilast, rolipram, and mesopram significantly reduced serum response factor (SRF) mRNA expression, whereas piclamilast and mesopram significantly inhibited myocardin-related transcription factor A (MRTFA) mRNA expression. Rolipram and roflumilast exhibited a decreasing trend in MRTFA mRNA expression without statistical significance. Notably, roflumilast demonstrated superior inhibitory effects, significantly decreasing both MRTF-A and SRF protein expression and effectively reducing nuclear localization of MRTF-A. Additionally, rolipram and roflumilast significantly attenuated TGF-\u03b21-induced phosphorylation of Smad2. These findings indicate that PDE4 inhibitors, particularly roflumilast, effectively suppress TGF-\u03b21-induced fibrogenic activation in HIMFs by modulating MRTF\/SRF and Smad-dependent pathways, highlighting the value of roflumilast for further preclinical investigation as a potential therapeutic strategy for intestinal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms27167126","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"7126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Roflumilast Inhibits Fibrogenic Activation in Human Intestinal Myofibroblasts via Inhibition of Myocardin-Related Transcription Factor\/Serum Response Factor Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1047-9452","authenticated-orcid":false,"given":"Dongju","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Jeong","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"},{"name":"Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0909-339X","authenticated-orcid":false,"given":"In Kyung","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeonghee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5802","authenticated-orcid":false,"given":"Duk Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Seoul Metropolitan Government\u2014Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hwan","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea"},{"name":"Institute of Basic Medical Sciences, CHA University School of Medicine, Seongnam 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1053\/j.gastro.2004.01.063","article-title":"Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences","volume":"126","author":"Loftus","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0889-8553(05)70056-X","article-title":"Epidemiology and the natural course of inflammatory bowel disease","volume":"28","author":"Andres","year":"1999","journal-title":"Gastroenterol. 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