Role of endoplasmic reticulum stress-mediated autophagy in cadmium-induced apoptosis in BRL-3A cells

Abstract

Cadmium (Cd), a widely present environmental toxicant, can cause liver damage following chronic exposure. Although endoplasmic reticulum stress (ERS) and autophagy are known to be involved in Cd-induced liver injury, their molecular mechanisms remain incompletely understood. In this study, using an in vitro Cd exposure model and pharmacological interventions, we investigated the mechanisms through which Cd induces autophagy via ERS and its interplay with apoptosis. We found that Cd-induced autophagosome accumulation was linked to the activation of ERS pathways (PERK/eIF2α/ATF4, IRE1α/JNK/Beclin1, and ATF6). Furthermore, this accumulation was also attributable to Cd-induced impairment of autophagic degradation, as evidenced by p62 accumulation. In addition, Cd exposure activates FAM134B-dependent ER-phagy, which requires ERS regulation. Finally, the autophagy activator rapamycin alleviated apoptosis, whereas the inhibitor chloroquine exacerbated it. In summary, our findings reveal a mechanism through which Cd coordinately regulates hepatocyte fate via ER stress-mediated, FAM134B-dependent ER-phagy and canonical autophagy, offering novel therapeutic targets and theoretical foundations for mitigating Cd toxicity.