{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:23:51Z","timestamp":1791087831935,"version":"4.1.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR074558"],"award-info":[{"award-number":["AR074558"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR080332"],"award-info":[{"award-number":["AR080332"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2210147"],"award-info":[{"award-number":["W81XWH2210147"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4\u2019-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5\u2019-bipyrimidine]-2,2\u2019-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3\/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-\u03b21)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (<jats:italic>e<\/jats:italic>.<jats:italic>g<\/jats:italic>., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-\u03b21-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.<\/jats:p>","DOI":"10.1371\/journal.pone.0306624","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T17:49:37Z","timestamp":1725644977000},"page":"e0306624","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["PIK-III exerts anti-fibrotic effects in activated fibroblasts by regulating p38 activation"],"prefix":"10.1371","volume":"19","author":[{"given":"Santiago","family":"Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron K.","family":"McDowell-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharaz B.","family":"Al-Meerani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan D.","family":"Cala-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Waich Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Ochsner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil J.","family":"McKenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay J.","family":"Celada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-9978","authenticated-orcid":true,"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan O.","family":"Rosas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-5427","authenticated-orcid":true,"given":"Konstantin","family":"Tsoyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"pone.0306624.ref001","doi-asserted-by":"crossref","first-page":"272","DOI":"10.3389\/fimmu.2015.00272","article-title":"Pathogenesis of Systemic Sclerosis.","volume":"6","author":"D Pattanaik","year":"2015","journal-title":"Front Immunol."},{"issue":"6","key":"pone.0306624.ref002","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1097\/00002281-200311000-00016","article-title":"Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies.","volume":"15","author":"ML Harris","year":"2003","journal-title":"Curr Opin Rheumatol."},{"issue":"10","key":"pone.0306624.ref003","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s00296-017-3826-y","article-title":"Determinants of mortality in systemic sclerosis: a focused review.","volume":"38","author":"DR Poudel","year":"2018","journal-title":"Rheumatol Int."},{"issue":"7","key":"pone.0306624.ref004","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/ard.2006.066068","article-title":"Changes in causes of death in systemic sclerosis, 1972\u20132002","volume":"66","author":"VD Steen","year":"2007","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"pone.0306624.ref005","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1136\/ard.62.2.146","article-title":"Predictors of end stage lung disease in a cohort of patients with scleroderma","volume":"62","author":"C Morgan","year":"2003","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"pone.0306624.ref006","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/art.40862","article-title":"Prevalence, Treatment, and Outcomes of Coexistent Pulmonary Hypertension and Interstitial Lung Disease in Systemic Sclerosis.","volume":"71","author":"A Young","year":"2019","journal-title":"Arthritis Rheumatol"},{"issue":"10103","key":"pone.0306624.ref007","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis.","volume":"390","author":"CP Denton","year":"2017","journal-title":"Lancet"},{"issue":"6","key":"pone.0306624.ref008","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1097\/00002281-200311000-00012","article-title":"Fibroblast and endothelial apoptosis in systemic sclerosis","volume":"15","author":"JB Jun","year":"2003","journal-title":"Curr Opin Rheumatol"},{"issue":"12","key":"pone.0306624.ref009","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/nrrheum.2014.137","article-title":"Transforming growth factor beta\u2014at the centre of systemic sclerosis","volume":"10","author":"R. 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