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Nevertheless, the molecular mechanisms underlying the pro\u2010regenerative effects of HGF\/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that,\n                    <jats:italic>Alb\u2010R26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>Met<\/jats:italic>\n                    <\/jats:sup>\n                    mice expressing a wild\u2010type\n                    <jats:italic>Met<\/jats:italic>\n                    transgene in albumin\u2010positive liver cells were fed with a 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC)\u2010supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC\u2010fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies using\n                    <jats:italic>Alb\u2010R26<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>Met<\/jats:italic>\n                    <\/jats:sup>\n                    liver\u2010derived hepatocytes under cholestasis\u2010simulated\n                    <jats:italic>in vitro<\/jats:italic>\n                    conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2\u2010related factor 2 (NRF2; encoded by the\n                    <jats:italic>Nfe2l2<\/jats:italic>\n                    gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF\u2010\u03b2)\u2010induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF\u2010\u03b2\u2010induced oxidative stress and apoptosis\n                    <jats:italic>in vitro<\/jats:italic>\n                    . In conclusion, our work evidences that moderate upregulation of wild\u2010type\u00a0MET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.\n                  <\/jats:p>","DOI":"10.1111\/febs.70315","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T16:32:17Z","timestamp":1763656337000},"page":"2370-2392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Moderate increase of\n                    <scp>MET<\/scp>\n                    in hepatocytes protects against cholestatic liver injury by promoting an effective antioxidant response"],"prefix":"10.1111","volume":"293","author":[{"given":"Carlos","family":"Gonz\u00e1lez\u2010Corralejo","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy 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