Histidine-rich glycoprotein

Histidine-rich glycoprotein (HRG) is a plasma glycoprotein with multiple ligand-binding capacities including heme, heparin, heparan sulfate, thrombospondin, and plasminogen (UniProt: P04196). It functions as an adapter protein regulating immune complex clearance, cell chemotaxis, adhesion, angiogenesis, coagulation, and fibrinolysis. HRG also modulates vascular endothelial growth factor signaling and can normalize tumor vessels to promote antitumor immunity.

In systemic biology, HRG is implicated in necrotic cell clearance through heparan sulfate-dependent phagocytosis and in immunoglobulin regulation. A genetic deficiency of HRG causes thrombophilia (THPH11; MIM 613116), underscoring its importance in hemostasis (UniProt: P04196).

HRG is downregulated in Alzheimer's disease brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.92 (Chaparral AD proteomics). This reduction was observed in post-mortem human AD brain across subcellular fractions using TMT-labeled mass spectrometry, suggesting potential relevance to AD pathophysiology, though the functional significance of reduced HRG in neurodegeneration remains to be clarified.