High mobility group box 1–receptor for advanced glycation end products signaling pathway (HMGB1/RAGE signaling pathway)

The high mobility group box 1–receptor for advanced glycation end products signaling pathway (HMGB1/RAGE signaling pathway) is a molecular cascade in which HMGB1, a nuclear DNA-binding protein and prototypic damage-associated molecular pattern (DAMP), is released from necrotic or stressed cells and binds to the cell surface receptor RAGE[3][7][6]. RAGE is a multiligand transmembrane receptor of the immunoglobulin superfamily, primarily expressed on endothelial and immune cells[6][1][10]. Their interaction triggers downstream signaling pathways including NF-κB, PI3K/Akt/mTOR, and MAPK, leading to the production of proinflammatory cytokines, cell migration, proliferation, tissue remodeling, and immune modulation[2][4][6][8]. This axis plays critical roles in the pathogenesis of cancer, inflammatory, cardiovascular, neurodegenerative, and autoimmune diseases[2][4][3][9][5]. Multiple drugs and biological agents targeting HMGB1 or RAGE are in development for therapeutic intervention, but challenges remain regarding specificity, safety, and compensation by parallel signaling pathways[4][9].

Other names

HMGB1-RAGE axisHMGB1–RAGE pathwayHigh mobility group box 1–RAGE signaling

Inhibition of HMGB1–RAGE binding, thereby blocking downstream inflammatory and pro-tumorigenic signaling Competitive antagonism at HMGB1 or RAGE Suppression of NF-κB and PI3K/AKT/mTOR signaling pathways Decoy receptor mechanism (soluble RAGE binds HMGB1, preventing cell-surface RAGE activation)