Arsenic promotes nonalcoholic steatohepatitis via MCFD2-induced PERK/eIF2α-mediated integrated stress response

Arsenic exposure, a typical environmental stressor, is closely associated with nonalcoholic steatohepatitis (NASH), but the definite mechanism remains elusive. The integrated stress response (ISR) acts as a core signaling cascade that mediates cellular stress responses and is implicated in the development of multiple metabolic disorders. Nevertheless, the critical regulatory role of ISR in the progression of arsenic-associated NASH has not been definitively clarified. In the present study, we verified the activation of ISR in arsenic-induced NASH by detecting the expression of ISR-related markers through in vivo and in vitro. Notably, the majority of the downstream impacts of the ISR were modified after arsenic exposure. However, of the four upstream ISR signaling initiators, only Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) was influenced, as evidenced by a marked elevation in PERK phosphorylation levels following arsenic treatment. Furthermore, we demonstrated that NaAsO₂ downregulated the protein levels of multiple coagulation factor deficiency protein 2 (MCFD2), which is localized on the endoplasmic reticulum and Golgi apparatus, in vivo and in vitro. Notably, overexpression of MCFD2 markedly attenuated PERK-eIF2α-mediated ISR, inflammation and lipid accumulation caused by arsenic in vitro. In conclusion, our findings reveal that arsenic exposure triggers the activation of PERK-eIF2α-mediated ISR and NASH by suppressing MCFD2. These findings may provide insights into the underlying mechanisms of NASH.