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The hepatotoxicity of PFOS has attracted particular attention, given the fact that the liver has one of the highest PFOS accumulations among human tissues. In this study, we revealed that subchronic PFOS exposure may exacerbate carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)\u2010induced liver fibrosis in animal models. Administration with 1\u00a0mg\/kg PFOS every other day for 56\u2009days dramatically enhanced CCl<jats:sub>4<\/jats:sub>\u2010mediated liver injury and hepatic stellate cell (HSC) activation. Furthermore, PFOS exposure may promote the activation of high\u2010mobility group box 1 (HMGB1)\/toll\u2010like receptor 4 (TLR4) signaling pathway through inducing the secretion of HMGB1 from hepatocytes. PFOS exposure induced the translocation of HMGB1 from the nucleus into the cytoplasm of hepatocytes and cultured BRL\u20103A cells at a starting concentration of 50\u2009\u03bcM. This process is accompanied with concurrent flux of calcium, suggesting a link between calcium signaling and HMGB1 release following PFOS exposure. Finally, we showed that PFOS\u2010exposed conditional medium (PFOS\u2010CM) of hepatocytes may induce the translocation of Smad2\/3 in HSCs in a TLR4\u2010dependent manner. Taken together, subchronic PFOS exposure might play a pro\u2010fibrotic role via a HMGB1\/TLR4\u2010dependent Smad signaling in HSCs. Our findings for the first time uncovered an involvement of PFOS exposure in liver fibrosis via HMGB1\/TLR4\/Smad signaling.<\/jats:p>","DOI":"10.1002\/tox.23458","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T14:25:48Z","timestamp":1641479148000},"page":"983-994","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Perfluorooctane sulfonate aggravates <scp>CCl4<\/scp>\u2010induced hepatic fibrosis via <scp>HMGB1<\/scp>\/<scp>TLR4<\/scp>\/Smad signaling"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-0989","authenticated-orcid":false,"given":"Chunhua","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health Nantong University  Nantong 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