British journal of pharmacology · 2025
Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis.
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Rastovic Una, Campinoti Sara, Wei Lai, Almeida Bruna, Bozzano Sergio Francesco, Amiri Ramin, Harris Nicola, Ajayi Omolola, Koay Tsin Shue, Kerins Caoimhe, Kenny Fiona N, Zamalloa Ane, Adofina Lissette, Miquel Rosa, Zen Yoh, Srinivasan Parthi, Menon Krishna, Heaton Nigel, Luni Camilla, Gentleman Eileen, Shaw Tanya, Ure Daren, Chokshi Shilpa, Urbani Luca, Palma Elena
Аннотация
BACKGROUND AND PURPOSE: Chronic liver disease and hepatic fibrosis constitute a threat to global health. 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-cyclophilin inhibitor (rencofilstat, RCF) in human models of fibrosis and alcohol-related liver disease.
EXPERIMENTAL APPROACH: RCF was tested in human precision-cut 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-derived matrix using proteomics, imaging and bioinformatic tools to study ECM alignment. PCLS stiffness upon treatment was assessed by atomic force microscopy.
KEY RESULTS: 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-treated HSC cultures reflected a less-stiff ECM, which was confirmed in the PCLS.
CONCLUSIONS AND IMPLICATIONS: 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.
EXPERIMENTAL APPROACH: RCF was tested in human precision-cut 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-derived matrix using proteomics, imaging and bioinformatic tools to study ECM alignment. PCLS stiffness upon treatment was assessed by atomic force microscopy.
KEY RESULTS: 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-treated HSC cultures reflected a less-stiff ECM, which was confirmed in the PCLS.
CONCLUSIONS AND IMPLICATIONS: 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.