RESUMEN
Cadmium (Cd) is a common heavy metal that is highly toxic to the liver, however, the exact mechanism underlying this damage accompanied by apoptosis has not been thoroughly demonstrated. In this study, we found that Cd exposure significantly reduced cell viability, including the increased populations of apoptotic cells and caspase-3/-7/-12 activation in HepG2 cells. Mechanistically, Cd initiated oxidative stress via elevating reactive oxygen species (ROS) levels, leading to oxidative damage in HepG2 cells. Simultaneously, Cd exposure induced endoplasmic reticulum (ER) stress via activating the protein kinase RNA-like ER kinase (PERK)-C/EBP homologous protein (CHOP) axis in HepG2 cells, and subsequently disturbed ER function as increased Ca2+ releasing from ER lumen. Intriguingly, further study revealed that oxidative stress is closely related with ER stress, as pretreatment with ROS scavenger, N-acetyl-l-cysteine (NAC) markedly reduced ER stress as well as protected ER function in Cd treated HepG2 cell. Collectively, these findings first revealed Cd exposure induced HepG2 cells death via a ROS-mediated PERK-CHOP-related apoptotic signaling pathway, which provides a novel insight into the mechanisms of Cd-induced hepatotoxicity. Furthermore, inhibitors for oxidative stress and ER stress might be considered as a new strategy to prevent or treat this disorder.