Precision targeting of pathological angiogenesis in liver cirrhosis: Molecular mechanisms and therapeutic translation challenges

Abstract

The core lethal complications of liver cirrhosis, particularly portal hypertension and hepatic decompensation, are closely linked to dysregulated pathological angiogenesis. Aberrant neovascularization is primarily driven by the hypoxia-inducible factor-vascular endothelial growth factor (VEGF) axis. Activated hepatic stellate cells release key factors like VEGF and platelet-derived growth factor, promoting endothelial cell proliferation. Inflammatory-oxidative stress signals (e.g., tumor necrosis factor-alpha/interleukin-6 and non-alcoholic fatty liver disease oxidase-derived reactive oxygen species) amplify this process via the nuclear factor kappa-B pathway. Activation of the local renin-angiotensin system also exacerbates vascular leakage and malformation through pathways like angiotensin II. Preclinical studies demonstrate that drugs targeting these pathways (e.g., the anti-VEGF agent bevacizumab, the multi-kinase inhibitor sorafenib) can effectively inhibit pathological angiogenesis. However, their clinical translation faces three major challenges: (1) Intrahepatic vascular heterogeneity limits targeting efficiency; (2) Activation of compensatory pathways (e.g., FGF/Notch) leads to treatment resistance; and (3) Systemic administration carries off-target risks. Future breakthroughs hinge on developing biomarkers based on single-cell sequencing, applying novel models like the “hepatic hypertension-chip”, and implementing multi-target combination therapies.

Keywords: Liver cirrhosis; Portal hypertension; Pathological angiogenesis; Vascular endothelial growth factor; Hepatic stellate cells; Targeted therapy; GPR116; LECT2-Tie1 signaling pathway; Hepatic hypertension-chip

Core Tip: This review systematically elaborates the central role of pathological angiogenesis in cirrhotic portal hypertension, focusing on molecular mechanisms such as the hypoxia-inducible factor-vascular endothelial growth factor axis, inflammatory stress, and local renin-angiotensin system activation. Although targeted therapies show excellent efficacy in preclinical studies, their clinical translation is hampered by three challenges: Vascular heterogeneity, activation of compensatory pathways, and risks associated with systemic administration. The article also highlights emerging strategies, including targeting novel mechanosensory receptors such as GPR116, combination therapies, and precision medicine models based on the “hepatic hypertension-chip”, which offer new perspectives for individualized treatment.