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The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective effect in several animal models of chronic liver injury that is related to its antifibrogenic and apoptotic action in HSC. In the present study, we evaluated whether autophagy is implicated in the hepatoprotective action of RPV, as autophagy plays an important role in HSC transdifferentiation. We employed two standard mouse models of chronic liver injury - fatty liver disease and carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced hepatotoxicity -and cultured HSC activated with the profibrotic cytokine TGF-\u03b2. RPV enhanced autophagy in the whole liver of both mouse models and in activated HSC, evident in the protein expression of autophagy markers, increased autophagosome content and lysosomal mass. Moreover, increased autophagic flux was observed in RPV-exposed HSC as revealed by tandem fluorescence<jats:italic>-<\/jats:italic>tagged LC3 and p62 and analysis of LC3-II accumulation in cells exposed to the lysosomal inhibitor chloroquine. Importantly, autophagy was involved in the cytotoxic effect of RPV on HSC, though in a differential manner. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) did not affect the diminishing effect of RPV on viability, while treatment with wortmannin or depletion of specific autophagy proteins (ATG5, Beclin-1 and SQSTM1\/p62) rescued the detrimental effect of high concentrations of RPV on the viability of activated HSC. Finally, we also provide evidence that RPV compromises the viability of TGF-\u03b2-induced HSC independently of its antifibrogenic effect, observed as reduced collagen 1A1 synthesis, and that this effect does not include RPV\u00b4s modulation of autophagy. In summary, as a contributor to the mechanisms involved in the hepatoprotective action of RPV, autophagy may be a good candidate to explore when developing novel therapeutics for LF.<\/jats:p>","DOI":"10.1038\/s41419-022-04789-7","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T20:03:20Z","timestamp":1650485000000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Implication of autophagy in the antifibrogenic effect of Rilpivirine: when more is less"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5173-7836","authenticated-orcid":false,"given":"Federico","family":"Lucantoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Benedicto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4411-829X","authenticated-orcid":false,"given":"Aleksandra","family":"Gruevska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1568-2342","authenticated-orcid":false,"given":"\u00c1ngela B.","family":"Moragrega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Fuster-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan V.","family":"Esplugues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-1470","authenticated-orcid":false,"given":"Ana","family":"Blas-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4487-2471","authenticated-orcid":false,"given":"Nadezda","family":"Apostolova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"4789_CR1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1146\/annurev-pathol-011110-130246","volume":"6","author":"V Hernandez-Gea","year":"2011","unstructured":"Hernandez-Gea V, Friedman SL. 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