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Long-term exposure to arsenic can cause liver injury and fibrosis. The activation of hepatic stellate cells (HSCs) plays an essential role in the process of liver fibrosis. We found that NaAsO 2 caused liver damage and fibrosis in vivo, accompanied by excessive collagen deposition and HSCs activation. In addition, NaAsO 2 upregulated autophagy flux, elevated the level of cytoplasmic cathepsin B (CTSB), and activated the NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome in a subtle way. Consistent with these findings in vivo, we demonstrated that NaAsO 2 -induced activation of HSCs depended on CTSB-mediated NLRP3 inflammasome activation in HSC-t6 cells and rats primary HSCs. Moreover, inhibition of autophagy decreased the cytoplasmic CTSB and alleviated the activation of the NLRP3 inflammasome, thereby attenuating the NaAsO 2 -induced HSCs activation. In summary, these results indicated that NaAsO 2 induced HSCs activation via autophagic-CTSB-NLRP3 inflammasome pathway. These findings may provide a novel insight into the potential mechanism of NaAsO 2 -induced liver fibrosis., (Copyright © 2019. Published by Elsevier Ltd.)

Abstract The activation of hepatic stellate cells (HSCs) is a key event in the development of hepatic fibrosis caused by arsenic. However, it is unclear how arsenic induces the activation of HSCs. In the present study, we found that arsenic trioxide (As 2 O 3) induced liver tissue damage, stimulated autophagy and HSCs activation, and increased collagen accumulation in the liver of mice. Supplemented with taurine (Tau) attenuated the changes mentioned above caused by As 2 O 3. In human hepatic stellate cell line LX-2 cells, we found that As 2 O 3 -induced activation of HSCs was autophagy-dependent, and we found that peroxisome proliferator activated receptors alpha (PPARα) played an important role in arsenic-induced HSCs activation. In addition, inhibiting autophagy and PPARα alleviated the activation of HSCs and lipid droplet loss induced by As 2 O 3. Moreover, we found that Tau alleviated As 2 O 3 -induced elevation of autophagy and PPARα expression, and activation of the HSCs. Our results indicated that autophagy was regulated by PPARα and was involved in lipid droplet loss during the activation of HSCs. Tau alleviated As 2 O 3 -induced HSCs activation by inhibiting the PPARα/autophagy pathway. These findings give an innovative insight into the association of PPARα, autophagy, the activation of HSCs and hepatic fibrosis induced by As 2 O 3. Highlights • As 2 O 3 -induced the activation of hepatic stellate cells was autophagy-dependent. • PPARα played an important role in arsenic-induced HSCs activation. • Taurine decreased the level of autophagy, and inhibited the activity of hepatic stellate cells. [ABSTRACT FROM AUTHOR]

• Ferroptosis existed in animal models of NaAsO 2 -induced pancreatic dysfunction. • NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy. • NaAsO 2 -induced ferroptosis involves MtROS, autophagy, ferritin. Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin. [ABSTRACT FROM AUTHOR]