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Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO<jats:sub>2<\/jats:sub> ingestion could result in liver fibrosis and oxidative stress in Sprague\u2013Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol\u2010requiring enzyme 1\u03b1 (IRE1\u03b1)\u2013endoplasmic reticulum (ER)\u2010stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO<jats:sub>2<\/jats:sub> exposure, and during ER stress, the IRE1\u03b1 pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1\u03b1 activation could attenuate the HSCs activation induced by NaAsO<jats:sub>2<\/jats:sub>. In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1\u03b1\/NOX4\u2010mediated ROS generation.<\/jats:p>","DOI":"10.1002\/jcp.29952","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T10:38:46Z","timestamp":1597055926000},"page":"1469-1480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["IRE1\u03b1\/NOX4 signaling pathway mediates ROS\u2010dependent activation of hepatic stellate cells in NaAsO<sub>2<\/sub>\u2010induced liver fibrosis"],"prefix":"10.1002","volume":"236","author":[{"given":"Ye","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Occupational and Environmental Health Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental 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