Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO₂ ingestion could result in liver fibrosis and oxidative stress in Sprague–Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol‐requiring enzyme 1α (IRE1α)–endoplasmic reticulum (ER)‐stress 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 NaAsO₂ exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO₂. In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4‐mediated ROS generation.

中文翻译：

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IRE1α/NOX4 信号通路介导 NaAsO2 诱导的肝纤维化中肝星状细胞的 ROS 依赖性激活。

肝纤维化是世界范围内严重的健康问题，其特征是肝星状细胞（HSCs）的活化和胶原蛋白的过度沉积。长期接触砷会导致 HSC 活化和肝纤维化。在本研究中，结果表明慢性 NaAsO ₂摄入可导致 Sprague-Dawley 大鼠的肝纤维化和氧化应激，以及代表性的胶原沉积和 HSC 激活。此外，肌醇需要酶1α（IRE1α）-内质网（ER）-应激途径被激活，烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）在大鼠肝脏中的活性上调。同时，活性氧（ROS）的过量产生可诱导HSCs活化，NOX4在体外产生ROS中起重要作用。此外，在NaAsO ₂暴露下，ER应激与HSC激活同时发生，并且在ER应激期间，IRE1α途径负责NOX4激活。因此，抑制 IRE1α 激活可以减弱 NaAsO ₂诱导的 HSCs 激活. 总之，本研究表明无机砷暴露可以通过 IRE1α/NOX4 介导的 ROS 生成激活 HSC。