Role of the NF-κB signaling pathway in vascular endothelial cell injury associated with metabolic dysfunction-associated steatotic liver disease under hypoxia.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), a complex multifactorial metabolic disorder, not only progresses to complications such as hepatic fibrosis, cirrhosis, and hepatocellular carcinoma but also is closely associated with extrahepatic diseases like cardiovascular disorders and type 2 diabetes, posing a significant threat to human health. MASLD represents an independent risk factor for cardiovascular events, which are the leading cause of death in adult MASLD patients. However, the pathophysiological mechanisms underlying the link between MASLD and cardiovascular diseases remain incompletely elucidated. Given the high prevalence of MASLD in hypoxic environments and the severity of its vascular sequelae, there is an urgent need to clarify the specific mechanisms by which MASLD mediates vascular endothelial injury under hypoxia. In this study, we constructed a MASLD mouse model via a high-fat diet and then exposed the mice to a hypoxic environment. We comprehensively evaluated metabolic parameters, hepatic pathological morphology, oxidative stress levels, vascular endothelial function-related factors, and key molecules of the NF-κB signaling axis. The results showed that hypoxia aggravated MASLD progression, potentially through mechanisms involving local hepatic inflammatory cascades, oxidative stress imbalance, and lipid metabolic disorders. Additionally, hypoxia activated the NF-κB signaling pathway, upregulating the expression of vascular endothelial adhesion molecules (ICAM-1, VCAM-1) and chemokines (MCP-1), thereby mediating vascular endothelial cell injury. This study demonstrates an association between high-fat diet-induced metabolic dysfunction and vascular endothelial injury under hypoxic conditions, with evidence suggesting the involvement of the NF-κB signaling pathway in the aorta.