Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 49

Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cells (HSC) activation and proliferation, hence modulating their fibrogenic potential is largely unknown. Here we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSC but parallels the increase of α-SMA and TGF-β during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, as their silencing or inhibition decreased HSC proliferation and the expression of phenotypic markers of HSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSC in response to PDGF. Moreover, during in vivo liver fibrogenesis by CCl4 administration, CtsB expression increased in HSC but not in hepatocytes, and its inactivation mitigated CCl4-induced inflammation, HSC activation and collagen deposition. Altogether, these findings support a critical role for cathepsins in HSC activation, suggesting that the antagonism of cathepsins in HSC may be of relevance for the treatment of liver fibrosis. Keyword