Heavy metal toxicity as a driver of endoplasmic reticulum stress and dysfunction

Heavy metals like lead, cadmium, arsenic, mercury and chromium are persistent environmental contaminants recognised for their harmful effects on human health. Among their various toxicological effects, recent studies have identified endoplasmic reticulum (ER) as a critical target of HM-induced cellular damage. This review explores the contribution of HMs in disrupting ER homeostasis, with a particular focus on ER dysfunctions, ER stress mechanisms, calcium regulation, and ER-mitochondria crosstalk. ER stress occurs when its protein-folding capacity is exceeded, activating the unfolded protein response (UPR). Persistent ER stress, commonly induced by HM exposure, triggers apoptosis and contributes to several neurological diseases. A central aspect of HM-mediated ER dysfunctions involves the imbalance of ER Ca²⁺ homeostasis, which disrupts cellular signalling and promotes oxidative stress. Additionally, HMs impair ER-mitochondrial communication and energy metabolism, eventually amplifying apoptotic signals. This review systematically explores how HMs contribute to ER stress by altering molecular chaperone expression, Ca²⁺ handling, and inter-organelle crosstalk. Furthermore, it explores the therapeutic potential of selected bioactive compounds, which have shown promising effects in mitigating HM-induced ER dysfunction. These compounds exert protective actions by modulating ER stress signalling pathways. Collectively, this review highlights the need for further studies on treating damage caused by heavy metals. Understanding the interplay between ER dysfunctions and HM toxicity offers valuable insights into the development of new and more advanced therapeutic approaches for neurodegenerative and other chronic diseases linked to toxic HM exposure.