Reactive oxygen species-endoplasmic reticulum stress pathway (ROS-ER pathway) (ROS-ER pathway)

The Reactive oxygen species (ROS)-endoplasmic reticulum (ER) pathway is a complex, bidirectional signaling network that regulates cellular proteostasis and redox balance (Zeeshan et al., 2016, Cell Death Dis). The ER serves as the primary site for the synthesis and folding of secretory and membrane proteins, a process highly sensitive to the cellular redox environment (Walter & Ron, 2011, Science). When the protein-folding capacity of the ER is overwhelmed, a condition known as ER stress occurs, activating the Unfolded Protein Response (UPR) to restore homeostasis or initiate apoptosis if the stress is terminal (Malhotra & Kaufman, 2007, Semin Cell Dev Biol). ROS production is intimately linked to this process, as protein disulfide bond formation in the ER generates hydrogen peroxide, and ER-calcium release can stimulate mitochondrial ROS production (Bhattarai et al., 2021, Antioxidants). Dysregulation of the ROS-ER axis is implicated in numerous pathologies, including cancer, where it can be exploited to induce tumor cell death, and neurodegenerative diseases, where chronic stress contributes to neuronal loss (Oakes & Papa, 2015, Annu Rev Pathol). Therapeutic strategies often involve small molecules that either inhibit ER-resident chaperones or modulate the antioxidant response to shift the balance toward cell death or survival depending on the clinical objective. For instance, proteasome inhibitors like Bortezomib induce lethal ER stress in multiple myeloma cells by causing an accumulation of misfolded proteins (Obeng et al., 2006, Blood).

Other names

ROS-ER stress axisOxidative stress-ER stress crosstalkUPR-ROS signaling axis

Drugs targeting this pathway typically act by either inducing proteotoxic stress and ROS accumulation to trigger apoptosis (e.g., in oncology) or by alleviating ER stress and oxidative damage to preserve cell viability (e.g., in neurodegeneration) (Bhattarai et al., 2021, Antioxidants).