LRG1 is a secreted leucine-rich glycoprotein that functions as a multivalent regulator of inflammation, angiogenesis, and fibrotic signaling. It binds to TGF-β receptors (type I and II) and modulates TGF-β/Smad pathway activation in a cell-type and context-dependent manner 1. Although constitutively expressed by hepatocytes and neutrophils, Lrg1-/- mice show no overt developmental abnormality, suggesting redundancy in homeostasis; however, LRG1 expression is induced by inflammatory stimuli (TNF-α, hypoxia) and directly promotes disease pathogenesis 1. In liver fibrosis, dysfunctional liver sinusoidal endothelial cells secrete LRG1, which activates hepatic stellate cells via paracrine TGF-β signaling 2. LRG1 promotes atherosclerosis progression by stimulating macrophage M1-like polarization through ERK1/2 and JNK pathways, with elevated circulating LRG1 detected in patients with coronary artery disease 3. Similarly, LRG1 amplifies tubulointerstitial fibrosis in kidney disease and glomerular TGF-β signaling in diabetes by enhancing Smad3 phosphorylation 45. In cerebral ischemia–reperfusion injury, LRG1 knockout improves neurological outcomes by restoring blood–brain barrier integrity and promoting anti-inflammatory macrophage phenotypes 6. Early cardiac repair post-myocardial infarction involves histone lactylation-driven Lrg1 expression in monocytes, supporting pro-angiogenic and anti-inflammatory functions 7. Preclinical evidence demonstrates that LRG1 inhibition via gene deletion or function-blocking antibodies attenuates disease progression across multiple conditions, supporting LRG1 as a biomarker and therapeutic target 1.