The Receptor for Advanced Glycation End-products (RAGE) is a transmembrane protein belonging to the immunoglobulin superfamily, first identified in 1992 for its role in binding AGEs—harmful compounds formed during prolonged hyperglycemia or oxidative stress. Structurally, RAGE contains a variable (V) domain, two constant-type (C1 and C2) domains, and a short cytoplasmic tail. It functions as a pattern recognition receptor, interacting with diverse ligands beyond AGEs, including HMGB1. S100 proteins, and amyloid-β, linking it to inflammation, immune responses, and chronic diseases.
RAGE activation triggers pro-inflammatory signaling pathways (e.g., NF-κB, MAPK) and oxidative stress, contributing to diabetic complications, neurodegenerative disorders, cancer progression, and cardiovascular diseases. Its soluble form (sRAGE), generated by alternative splicing or proteolytic cleavage, acts as a decoy receptor to neutralize ligands, offering therapeutic potential.
RAGE-targeting antibodies are critical tools in research and drug development. They enable detection of RAGE expression in tissues, inhibition of ligand-receptor interactions, and modulation of downstream signaling. Therapeutic anti-RAGE antibodies aim to block pathological pathways in conditions like diabetic nephropathy or atherosclerosis. Challenges include RAGE's pleiotropic roles—its dual pro-survival and pro-inflammatory effects vary by cellular context—requiring precise targeting to avoid unintended consequences. Current studies focus on isoform-specific antibodies and combination therapies to optimize clinical outcomes.