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

Table 1 Major therapeutic strategies for targeting pathological angiogenesis in liver cirrhosis

Therapeutic strategy category	Representative drug/method	Primary target/mechanism	Development stage and evidence level	Key findings and existing challenges
Anti-VEGF therapy	Bevacizumab	Neutralizes circulating VEGF, blocking the VEGFR2 signaling pathway	Preclinical studies (e.g., CCl4-induced rat models): Reduces liver VEGF expression and portal pressure[28]. Phase II clinical trial: Showed reduction in hepatic venous pressure gradient, but with potential adverse effects like hypertension and proteinuria[29]	Findings: Effective in reducing portal pressure in animal models. Challenges: Clinical application is limited by systemic adverse effects (e.g., hypertension), particularly in portal hypertension patients, requiring caution
Multi-kinase inhibitor	Sorafenib	Inhibits multiple targets including VEGFR, PDGFR, Raf	Phase III clinical trials (approved for HCC). Trial in Child-Pugh B cirrhosis patients (REVERT): Did not significantly improve survival[50,51]	Findings: Improves sinusoidal capillarization in animal models. Challenges: Limited efficacy in advanced cirrhosis patients, indicating disease-stage dependent effectiveness
Targeting novel mechanisms	Targeting GPR116 (e.g., shRNA)	Inhibits the mechanosensor GPR116, protecting vascular integrity	Preclinical research (HH-Chip model and animal experiments)[34]	Findings: In the HH-Chip and animal models, inhibiting GPR116 alleviates pressure-induced LSEC injury and fibrosis, representing a shift from “anti-angiogenesis” to “anti-vascular regression”. Challenges: Early stage
Traditional Chinese medicine formula	Roucongrong granule (or equivalent)	Multi-target: Modulates LSEC lipid metabolism (CD36/PPAR pathway), inhibits HSC activation[52]	Preclinical research (animal models)	Findings: In CCl4-induced mouse cirrhosis model, improves liver microcirculation, inhibits HSC activation, downregulates VEGF/CD34 expression, showing multi-target synergistic effects. Challenges: Precise components/mechanisms and clinical trial evidence needed
Combination therapy	Anti-VEGF drug + anti-inflammatory drug (e.g., TNF-α inhibitor)	Simultaneously blocks angiogenesis and inflammation pathways	Preclinical research	Findings: Shows synergistic effects superior to monotherapy in animal models, more effectively reducing portal pressure. Challenges: Optimal combinations/timing and potential added toxicity need exploration
Interventional local delivery	Local VEGFR2 inhibitor post-TIPS	Local high-concentration delivery, reducing systemic toxicity	Exploratory research	Findings: Aims to reduce endothelial hyperplasia in TIPS shunt tracts, lowering restenosis risk[20,53]. Challenges: Delivery technology, carrier selection, and local safety are key issues

VEGF: Vascular endothelial growth factor; TNF-α: Tumor necrosis factor-alpha; VEGFR2: Vascular endothelial growth factor receptor 2; PDGFR: Platelet-derived growth factor receptor; Raf: Rapidly accelerated fibrosarcoma (kinase); HCC: Hepatocellular carcinoma; TIPS: Transjugular intrahepatic portosystemic shunt; LSEC: Liver sinusoidal endothelial cell; HSC: Hepatic stellate cell.