{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:13:57Z","timestamp":1790507637289,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001729","name":"Stiftelsen f\u00f6r\u00a0Strategisk Forskning","doi-asserted-by":"publisher","award":["ID17-0107"],"award-info":[{"award-number":["ID17-0107"]}],"id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGF\u03b21-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.<\/jats:p>","DOI":"10.3390\/cells8111409","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T11:30:19Z","timestamp":1573212619000},"page":"1409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-0006","authenticated-orcid":false,"given":"Sonia","family":"Sim\u00f3n Serrano","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Translational Cancer Research, Lund University, Medicon Village, 223 63 Lund, Sweden"},{"name":"NeuroVive Pharmaceutical AB, 223 63 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvar","family":"Gr\u00f6nberg","sequence":"additional","affiliation":[{"name":"NeuroVive Pharmaceutical AB, 223 63 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Longato","sequence":"additional","affiliation":[{"name":"Engitix Ltd., London NW3 2PF, UK"},{"name":"Regenerative Medicine &amp; Fibrosis Group, Institute for Liver &amp; Digestive Health, University College London, Royal Free Hospital, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Rombouts","sequence":"additional","affiliation":[{"name":"Engitix Ltd., London NW3 2PF, UK"},{"name":"Regenerative Medicine &amp; Fibrosis Group, Institute for Liver &amp; Digestive Health, University College London, Royal Free Hospital, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gregory","sequence":"additional","affiliation":[{"name":"Isomerase Therapeutics Ltd., Cambridge CB10 1XL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Moss","sequence":"additional","affiliation":[{"name":"Isomerase Therapeutics Ltd., Cambridge CB10 1XL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eskil","family":"Elm\u00e9r","sequence":"additional","affiliation":[{"name":"NeuroVive Pharmaceutical AB, 223 63 Lund, Sweden"},{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mazza","sequence":"additional","affiliation":[{"name":"Engitix Ltd., London NW3 2PF, UK"},{"name":"Regenerative Medicine &amp; Fibrosis Group, Institute for Liver &amp; Digestive Health, University College London, Royal Free Hospital, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gallay","sequence":"additional","affiliation":[{"name":"Department of Immunology &amp; Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Pinzani","sequence":"additional","affiliation":[{"name":"Engitix Ltd., London NW3 2PF, UK"},{"name":"Regenerative Medicine &amp; Fibrosis Group, Institute for Liver &amp; Digestive Health, University College London, Royal Free Hospital, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-0638","authenticated-orcid":false,"given":"Magnus J.","family":"Hansson","sequence":"additional","affiliation":[{"name":"NeuroVive Pharmaceutical AB, 223 63 Lund, Sweden"},{"name":"Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8875-6440","authenticated-orcid":false,"given":"Ramin","family":"Massoumi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Cancer Research, Lund University, Medicon Village, 223 63 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.bpg.2011.02.010","article-title":"Fibrosis in alcoholic and nonalcoholic steatohepatitis","volume":"25","author":"Bataller","year":"2011","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/liv.12465","article-title":"Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: More complicated than ever","volume":"34","author":"Carloni","year":"2014","journal-title":"Liver Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3389\/fphar.2014.00167","article-title":"The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies","volume":"5","author":"Xu","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s40139-013-0018-7","article-title":"Reversibility of Liver Fibrosis and Inactivation of Fibrogenic Myofibroblasts","volume":"1","author":"Liu","year":"2013","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1053\/gast.2002.33367","article-title":"Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C","volume":"122","author":"Arthur","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1056\/NEJM200102083440604","article-title":"Regression of Liver Fibrosis after Biliary Drainage in Patients with Chronic Pancreatitis and Stenosis of the Common Bile Duct","volume":"344","author":"Ratouis","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jhbp.245","article-title":"Recent advancement of molecular mechanisms of liver fibrosis","volume":"22","author":"Seki","year":"2015","journal-title":"J. Hepato Biliary Pancreat. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1053\/j.gastro.2012.06.036","article-title":"Deactivation of hepatic stellate cells during liver fibrosis resolution in mice","volume":"143","author":"Troeger","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/j.1440-1746.2006.04584.x","article-title":"Hepatic stellate cells and the reversal of fibrosis","volume":"21","author":"Kisseleva","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/aja.1001320404","article-title":"\u201cSternzellen\u201d in the liver: Perisinusoidal cells with special reference to storage of vitamin A","volume":"132","author":"Wake","year":"1971","journal-title":"Am. J. Anat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.addr.2017.05.018","article-title":"Engineering in vitro models of hepatofibrogenesis","volume":"121","author":"Mazza","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5534","DOI":"10.1038\/s41598-017-05134-1","article-title":"Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization","volume":"7","author":"Mazza","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Davis, T.L., Walker, J.R., Campagna-Slater, V., Finerty, P.J., Paramanathan, R., Bernstein, G., MacKenzie, F., Tempel, W., Ouyang, H., and Lee, W.H. (2010). Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000439"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/gb-2005-6-7-226","article-title":"The cyclophilins","volume":"6","author":"Wang","year":"2005","journal-title":"Genome Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3233\/CBM-170142","article-title":"Cyclophilin A was revealed as a candidate marker for human oral submucous fibrosis by proteomic analysis","volume":"20","author":"Hou","year":"2017","journal-title":"Cancer Biomark."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"657","DOI":"10.2119\/molmed.2015.00076","article-title":"Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia","volume":"21","author":"Iordanskaia","year":"2015","journal-title":"Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/j.1440-1746.2010.06406.x","article-title":"N-methyl-4-isoleucine cyclosporine attenuates CCl -induced liver fibrosis in rats by interacting with cyclophilin B and D","volume":"26","author":"Wang","year":"2011","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Heinzmann, D., Bangert, A., M\u00fcller, A.-M., Von Ungern-Sternberg, S.N.I., Emschermann, F., Sch\u00f6nberger, T., Chatterjee, M., Mack, A.F., Klingel, K., and Kandolf, R. (2015). The Novel Extracellular Cyclophilin A (CyPA) \u2014Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124606"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1111\/j.1478-3231.2007.01560.x","article-title":"NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells","volume":"27","author":"Kohjima","year":"2007","journal-title":"Liver Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/hep.20437","article-title":"Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes","volume":"40","author":"Kon","year":"2004","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0092-8674(91)90124-H","article-title":"Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes","volume":"66","author":"Liu","year":"1991","journal-title":"Cell"},{"key":"ref_23","first-page":"852","article-title":"Cyclosporine A Protects Against Primary Biliary Cirrhosis Recurrence After Liver Transplantation","volume":"10","author":"Wasilenko","year":"2010","journal-title":"Arab. Archaeol. Epigr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1124\/jpet.108.143578","article-title":"NIM811 (N-methyl-4-isoleucine cyclosporine), a mitochondrial permeability transition inhibitor, attenuates cholestatic liver injury but not fibrosis in mice","volume":"327","author":"Rehman","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1124\/jpet.119.261099","article-title":"A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models","volume":"371","author":"Kuo","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.chembiol.2014.10.023","article-title":"Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection","volume":"22","author":"Hansson","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"Fujii","year":"2013","journal-title":"Med. Mol. Morphol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1194\/jlr.M300450-JLR200","article-title":"Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator","volume":"45","author":"Miao","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.ejphar.2017.11.021","article-title":"Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-Induced NASH (DIN) hamster model","volume":"818","author":"Briand","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T))","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_33","first-page":"956","article-title":"Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial","volume":"385","author":"Loomba","year":"2014","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1038\/s41598-019-40322-1","article-title":"Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan","volume":"9","author":"Park","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1073\/pnas.89.8.3511","article-title":"Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages","volume":"89","author":"Sherry","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/1440-1681.12881","article-title":"Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney","volume":"45","author":"Hou","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.3389\/fphar.2019.01129","article-title":"Cyclophilin Inhibitor NV556 Reduces Fibrosis and Hepatocellular Carcinoma Development in Mice With Non-Alcoholic Steatohepatitis","volume":"10","author":"Kuo","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1093\/hmg\/ddr037","article-title":"Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes","volume":"20","author":"Pyott","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Cabral, W.A., Perdivara, I., Weis, M., Terajima, M., Blissett, A.R., Chang, W., Perosky, J.E., Makareeva, E.N., Mertz, E.L., and Leikin, S. (2014). Abnormal Type I Collagen Post-translational Modification and Crosslinking in a Cyclophilin B KO Mouse Model of Recessive Osteogenesis Imperfecta. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004465"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/S0021-9258(17)35315-2","article-title":"Cyclosporin A slows collagen triple-helix formation in vivo: Indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase","volume":"266","author":"Steinmann","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1096\/fj.14-268425","article-title":"Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice","volume":"30","author":"Liu","year":"2015","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1073\/pnas.61.2.708","article-title":"The cross-linking of collagen and elastin: Enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone","volume":"61","author":"Pinnell","year":"1968","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:32:59Z","timestamp":1760189579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/11\/1409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,8]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cells8111409"],"URL":"https:\/\/doi.org\/10.3390\/cells8111409","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,8]]}}}