The role of endoplasmic reticulum stress-mediated autophagy in cadmium-induced liver injury in rats.

Cadmium (Cd) is a widespread toxicant with high bioaccumulation potential. This study explores the interplay of endoplasmic reticulum stress (ERS), autophagy, and apoptosis in Cd-induced hepatotoxicity, focusing on whether ERS-driven autophagy protects against liver injury. Male SD rats (4 weeks old, n = 24) were acclimatized for 7 days and randomized into four groups receiving CdCl₂ at doses of 0, 0.5, 1, or 2 mg/kg for 14 consecutive days. A second cohort (n = 36) was similarly allocated to six groups: control, Cd, 4-PBA, Cd + 4-PBA, CQ and Cd + CQ. All treatments were administered via daily intraperitoneal injection throughout the study. On day 14, blood and liver tissues were collected for analyses of liver function, hematological parameters, and histopathology. The expression of target factors was analyzed via qRT-PCR and Western blotting. Results indicate that Cd exposure causes liver injury and disordered hepatocyte morphology. ERS markers Grp78 and Caspase-12 and autophagy-related factors Beclin-1, Atg5, P62 and LC3 are upregulated at both mRNA and protein levels. The endoplasmic reticulum-phagy (ER-phagy) receptor FAM134B and the apoptosis effector cleaved Caspase3 are upregulated at the protein level. These findings indicate that Cd induces ERS, UPR activation, autophagy, reticulophagy, and apoptosis. The ERS inhibitor 4-PBA markedly attenuated Cd-induced hepatic injury. Compared with the Cd group, the Cd + 4-PBA group showed decreased serum ALT and AST levels, as well as reduced RBC, WBC, MCH, and MCV counts. At the molecular level, mRNA and protein expression of ER stress markers Grp78, Caspase-12, PERK, eIF2α, ATF4, IRE1α, JNK, and ATF6 were all downregulated. Protein levels of the ER-phagy receptor FAM134B and the apoptosis effector cleaved Caspase-3 were also decreased. The autophagy inhibitor CQ aggravated such injury. Compared with the Cd group, the Cd + CQ group showed increased serum ALT and AST levels, as well as elevated RBC, MCH, and MCV counts. At the protein level, expression of the autophagy-related factors P62 and LC3, and the apoptosis effector cleaved Caspase-3 was significantly increased. These results show that Cd-induced ERS activates autophagy and reticulophagy mainly via the PERK, IRE1α, and ATF6 pathways, and this adaptive response clears autophagic substrates to alleviate hepatocyte damage.