The receptor for advanced glycation end products (RAGE) is a multiligand pattern-recognition receptor composed of extracellular V-, C1-, and C2-type immunoglobulin domains, a single transmembrane region, and a cytoplasmic tail that is essential for intracellular signal transduction (1). RAGE interacts with a broad spectrum of ligands, including advanced glycation end products (AGEs), S100/calgranulin proteins, and high-mobility group box 1 (HMGB1), thereby functioning as a potent amplifier of inflammatory signaling across multiple tissues (1,2). In addition, RAGE exists in soluble forms (sRAGE) that lack transmembrane and cytoplasmic domains and can competitively bind RAGE ligands, acting as decoy receptors that modulate RAGE-dependent signaling (1). Under physiological conditions, RAGE expression is low in most adult tissues, with the notable exception of the lung, where it is abundantly expressed on alveolar epithelial cells and alveolar macrophages (3,4). In the context of acute lung injury, RAGE plays a central role in mediating inflammatory responses, and therapeutic blockade of RAGE after injury has been shown to significantly attenuate inflammation and tissue damage in experimental models (4). Beyond pulmonary pathology, aberrant activation of RAGE and sustained engagement by its ligands have been implicated in a wide range of inflammatory and degenerative diseases, including diabetes, Alzheimer’s and Parkinson’s disease, multiple sclerosis, stroke, and various forms of cancer (5).
