TEX264-mediated ER-phagy dysfunction contributes to Cadmium-induced ER stress: Implication of hippocampal neuronal apoptosis and cognitive deficits.

Cadmium (Cd), a well-recognized neurotoxicant, elicits neuronal death and cognitive impairment. Cd cytotoxicity disrupts endoplasmic reticulum (ER) proteostasis, leading to the accumulation of misfolded and unfolded proteins and subsequent ER stress-mediated apoptosis. Endoplasmic reticulum autophagy (ER-phagy) serves as a crucial quality-control mechanism that resolves excessive ER stress and maintains ER homeostasis. However, the precise roles of ER-phagy, ER stress-mediated apoptosis, and their crosstalk in Cd-induced neurotoxicity remain poorly defined. Here, we demonstrated that Cd exposure robustly induces ER stress and the subsequent apoptotic injury in the mouse hippocampus and HT-22 hippocampal neurons. Pharmacological inhibition of ER stress with 4-phenylbutyric acid (4-PBA) effectively rescued Cd-triggered neuronal damage, reduced cell death, and ameliorated Cd-associated cognitive deficits. Notably, Cd exposure leads to pronounced ER-phagy dysfunction, as evidenced by decreased LC3-II accumulation, elevated calnexin levels, and impaired ER-phagy autophagic flux in vivo and in vitro. Furthermore, the ER-phagy receptor TEX264 was downregulated under Cd stress. Importantly, restoration of ER-phagy via overexpressing TEX264 markedly mitigated Cd-elicited ER stress, thereby blocking the downstream apoptotic cascade. Collectively, our findings identify impaired ER-phagy as a previously unrecognized mechanism underlying Cd neurotoxicity, which synergizes with ER stress-mediated apoptosis to promote hippocampal neuronal injury. These results highlight ER quality control pathways as promising therapeutic targets for the intervention of Cd-induced cognitive and neuronal damage.