Hepassocin drives EGFR-dependent endothelial atherogenic activation via NOX1/ROS amplification and p38 signaling

Metabolic stress results in the production of circulating hepatokines that can be coupled to hepatic injury and vascular dysfunction, but the underlying biochemical signaling routes remain incompletely defined. Hepassocin (HPS; FGL1) is a hepatocyte-derived factor implicated in metabolic inflammation; however, whether it directly programs endothelial pro-atherogenic signaling is unclear. Here, we report that a high-fat diet (HFD) increases serum HPS and that palmitate induces oxidative stress-dependent HPS expression and release from hepatocytes, as these responses are reversed by N-acetylcysteine (NAC). Recombinant HPS directly drives endothelial injury and activation in human umbilical vein endothelial cells (HUVECs), increasing ROS levels and lipid peroxidation (MDA/H₂O₂), promoting Apoptosis, and enhancing adhesion molecule expression and monocyte-endothelial adhesion. Mechanistically, HPS activates EGFR and engages a redox-amplifying EGFR-NOX1 module characterized by the induction of NOX1 and p22phox, leading to robust oxidative stress signaling. EGFR or NOX1 silencing abolishes HPS-induced redox stress and atherogenic endothelial phenotypes. In parallel, HPS activates p38 downstream of EGFR, and p38 suppression mitigates HPS-driven endothelial activation and monocyte adhesion independent of ROS amplification, revealing a second mechanism. Together, these data define dual, targetable pathways-HPS-EGFR-NOX1/ROS and HPS-EGFR-p38-that mechanistically connect a liver-derived circulating factor to endothelial dysfunction and immune cell recruitment, positioning HPS-EGFR signaling as a tractable axis for metabolic stress-associated vascular disease.

Atherogenesis; EGFR; Endothelial dysfunction; Hepassocin; NOX1; Reactive Oxygen Species (ROS).