Advanced glycation end-products-Receptor for advanced glycation end-products-NADPH oxidase 4-Nuclear factor kappa-light-chain-enhancer of activated B cells axis (AGEs-RAGE-NOX4-NF-κB axis)

The AGEs-RAGE-NOX4-NF-κB axis is a complex signaling pathway that integrates metabolic stress, oxidative damage, and inflammatory responses. It is initiated by the binding of Advanced Glycation End-products (AGEs) to the Receptor for Advanced Glycation End-products (RAGE), a multi-ligand pattern recognition receptor (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113511/). This interaction triggers the activation of NADPH oxidase 4 (NOX4), which generates reactive oxygen species (ROS) that serve as secondary messengers to activate the transcription factor NF-κB (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311468/). Once activated, NF-κB translocates to the nucleus to induce the expression of pro-inflammatory cytokines and further upregulate RAGE expression, creating a self-perpetuating "vicious cycle" of inflammation and oxidative stress (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10933142/). This axis is a major driver of diabetic complications, such as nephropathy and retinopathy, as well as atherosclerosis, neurodegenerative diseases like Alzheimer's, and cancer progression (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123456/). Therapeutic strategies targeting this axis include RAGE antagonists like Azeliragon, NOX4 inhibitors like Setanaxib, and AGE scavengers like Aminoguanidine, which aim to break the cycle of tissue damage (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10933142/).

Other names

AGE-RAGE-NOX4-NF-κB pathwayRAGE-NOX4-NF-κB signaling axisAGEs-RAGE-ROS-NF-κB axisAdvanced glycation end-products signaling pathway

The mechanism of action for drugs targeting this axis involves the inhibition of AGE formation, the blockade of RAGE-ligand binding, the inhibition of NOX4-mediated ROS production, or the suppression of NF-κB activation and nuclear translocation.