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Clinical translation of preclinical research has been limited, highlighting an urgent need for novel treatments. Cyclophilin inhibitors have shown beneficial effects in liver disease; however, the underlying mechanism of action and the effect across different aetiologies remain elusive. Here, we investigate the impact of a pan\u2010cyclophilin inhibitor (rencofilstat, RCF) in human models of fibrosis and alcohol\u2010related liver disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>RCF was tested in human precision\u2010cut liver slices (PCLS) and primary human hepatic stellate cells (HSCs). Fibrosis and cell activation were assessed using transcriptomic and protein analysis. A comprehensive characterisation of changes in extracellular matrix (ECM) biochemical and structural composition was performed in PCLS and HSC\u2010derived matrix using proteomics, imaging and bioinformatic tools to study ECM alignment. PCLS stiffness upon treatment was assessed by atomic force microscopy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Transcriptomic and proteomic analyses of PCLS revealed a dramatic impact of RCF on ECM organisation and remodelling. Biochemical composition and fibre alignment analysis of the ECM obtained from HSCs showed a reduction in the amount of ECM core proteins and associated enzymes by RCF, reshaping the architecture of matrix fibres without affecting the HSC activation. The disordered matrix detected in RCF\u2010treated HSC cultures reflected a less\u2010stiff ECM, which was confirmed in the PCLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>This work provides evidence for a novel mechanism linking cyclophilins and ECM remodelling in advanced 3D models of liver disease, with potential applications in therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70139","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T02:41:18Z","timestamp":1753756878000},"page":"5647-5669","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol\u2010related liver fibrosis"],"prefix":"10.1111","volume":"182","author":[{"given":"Una","family":"Rastovic","sequence":"first","affiliation":[{"name":"Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London Foundation for Liver Research and King's College Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Campinoti","sequence":"additional","affiliation":[{"name":"Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London Foundation for Liver Research and King's College Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai","family":"Wei","sequence":"additional","affiliation":[{"name":"Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London 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