Reactive oxygen species-mediated endoplasmic reticulum stress-JNK apoptotic signaling pathway (ROS/ER stress/JNK pathway)

The Reactive oxygen species (ROS) pathway / ER stress–JNK apoptotic signaling axis is a complex signaling network that mediates programmed cell death in response to physiological and environmental stressors. It begins with the accumulation of ROS, which causes oxidative damage to proteins and lipids within the endoplasmic reticulum (ER), leading to a state of ER stress characterized by the accumulation of misfolded proteins (Zeeshan et al., 2016, Journal of Clinical & Cellular Immunology). This stress activates the Unfolded Protein Response (UPR), specifically the IRE1α branch, which recruits TRAF2 and ASK1 to activate c-Jun N-terminal kinase (JNK) (Dhanasekaran & Reddy, 2008, Oncogene). Activated JNK then translocates to the mitochondria or nucleus to promote apoptosis by inhibiting anti-apoptotic Bcl-2 and activating pro-apoptotic proteins like Bim and the transcription factor CHOP (Szegezdi et al., 2006, EMBO Reports). In therapeutic contexts, this pathway is a major target for anti-cancer agents like Bortezomib, which induces proteotoxic stress and ROS to trigger apoptosis in malignant cells (Obeng et al., 2006, Blood). However, chronic activation of this pathway is also implicated in the pathogenesis of neurodegenerative diseases like Alzheimer's and Parkinson's, where it contributes to neuronal loss (Yuan et al., 2017, Molecular Neurobiology).

Other names

ROS-ER stress-JNK axisOxidative stress-induced ER stress-JNK signalingUPR-JNK apoptotic pathwayIRE1-ASK1-JNK signaling cascade

Drugs targeting this pathway typically act by either inducing ROS and ER stress to trigger apoptosis in cancer cells (e.g., proteasome inhibitors) or by inhibiting JNK and oxidative stress to prevent pathological cell death in neurodegenerative or inflammatory conditions.