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 TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.
Keywords: 3D in vitro model; NV556; STAM; cyclophilin; decellularized human liver; hepatic stellate cells (HSC); liver fibrosis; methionine-choline-deficient (MCD) diet; nonalcoholic steatohepatitis.
Conflict of interest statement
S.S.S., A.G., E.E., and M.J.H are employees of NeuroVive Pharmaceutical AB, which develops NV556. S.S.S., A.G., E.E., and M.J.H. own shares in NeuroVive Pharmaceutical AB. L.L. and G.M. are employees of Engitix Ltd., which develops proprietary 3D extracellular matrix technology. K.R. and M.P. receive consultancies from Engitix Ltd., and G.M., K.R., L.L., and M.P. own shares in Engitix Ltd. M.G. and S.M. are employees of and own shares in Isomerase Therapeutics Ltd. J.K., P.G., and R.M. have nothing to disclose.
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