{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T04:46:59Z","timestamp":1777351619173,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 DK130949"],"award-info":[{"award-number":["R01 DK130949"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30 DK120531"],"award-info":[{"award-number":["P30 DK120531"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background\/Aim: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474\/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). Methods: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription\u2013polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18\/24\/36\/120\/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL\/6 mice, and the fibrosis progression was studied. Results: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-\/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. Conclusions: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.<\/jats:p>","DOI":"10.3390\/cells13070649","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T12:01:22Z","timestamp":1712577682000},"page":"649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Antagonizing Activin A\/p15INK4b Signaling as Therapeutic Strategy for Liver Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Sowmya","family":"Mekala","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-3811","authenticated-orcid":false,"given":"Ravi","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha Loretta","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bill","family":"Bowen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George K.","family":"Michalopoulos","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Locker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reben","family":"Raeman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Oertel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street\u2014BST S-404, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.3390\/cells1041261","article-title":"Signals and cells involved in regulating liver regeneration","volume":"1","author":"Kang","year":"2012","journal-title":"Cells"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.ajpath.2018.03.008","article-title":"Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine","volume":"188","author":"Gilgenkrantz","year":"2018","journal-title":"Am. 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