Hepatokine FGL1 drives endothelial injury and atherogenesis via integrin β1-mediated endothelial-mesenchymal...

Atherosclerosis is driven by metabolic dysregulation and endothelial dysfunction; however, the precise molecular mechanisms underlying its pathogenesis remain incompletely elucidated. Fibrinogen-like protein 1 (FGL1) is a well-established hepatokine with critical roles in regulating tumorigenesis and metabolic dysfunction, while its involvement in atherogenesis remains unclear. Our clinical and preclinical studies revealed elevated plasma FGL1 levels in atherosclerotic patients and mice, correlating with arterial stenosis severity. Prolonged high-fat diet exposure specifically upregulated hepatic FGL1 expression. Hepatic FGL1 overexpression accelerated atherosclerosis, while liver-specific knockdown reduced plaque burden. Exogenous administration of FGL1 accelerated endothelial injury and atherosclerosis progression. Mechanistically, liver-derived FGL1 accumulates in vascular endothelium through fibrinogen C-terminal domain Trp225-mediated binding to integrin β1's vWFA domain. This interaction promotes the conformational change of integrin β1 and the formation of integrin β1/ILK1 complex, co-activating FAK/ERK and Smad signaling to drive transcriptional reprogramming of endothelial cells. Therapeutic interventions targeting FGL1-integrin β1 axis by integrin β1 blocking antibody, FGL1-neutralizing antibody, or RGD peptide effectively attenuated endothelial injury and atherogenic progression in murine models. These findings establish hepatic FGL1 as a novel endocrine regulator of vascular pathophysiology, highlighting the FGL1-integrin β1 axis as a promising therapeutic target for endothelial protection and atherosclerosis management.