Histidine-rich glycoprotein (HRG) is a plasma glycoprotein with multifaceted regulatory functions in hemostasis, inflammation, and immune homeostasis. HRG binds multiple ligands including heparin, heparan sulfate, plasminogen, and thrombospondin in a zinc-dependent manner, functioning as an adapter protein in numerous physiological processes. In coagulation, HRG neutralizes glycosaminoglycans through zinc-coordinated histidine residues, with zinc ions enhancing HRG's affinity for heparan sulfate and heparin 1. HRG regulates immune responses by facilitating clearance of necrotic cells and immune complexes while inhibiting angiogenesis through modulation of VEGF signaling pathways. During sepsis, HRG maintains neutrophil quiescence and suppresses vascular endothelial cell activation, reducing adhesion molecules and cytokine secretion, with plasma HRG levels serving as a sepsis severity biomarker 2. In hepatic disease, HRG levels increase with MASLD/MASH progression and fibrosis severity, promoting hepatocellular carcinoma development through macrophage polarization and pro-inflammatory responses 3. HRG deficiency causes thrombophilia, while elevated HRG correlates with worse outcomes in HCC patients. These findings establish HRG as a critical regulator of hemostasis, inflammation, and carcinogenesis with potential clinical utility as a biomarker and therapeutic target.