Hepatic Senp2 deletion resolves the angiogenic switch in fibrosis via β-catenin/LECT2

Liver fibrosis can arise from diverse etiologies, including metabolic stress and nutritional deficiencies. The methionine- and choline-deficient (MCD) diet induces liver fibrosis independent of metabolic syndrome, offering a model to study non-metabolic drivers of hepatic fibrogenesis. SUMO-specific protease 2 (SENP2) has been implicated in metabolic liver disease, but its role in nutritionally induced fibrosis remains unknown. Here, we investigated how hepatic Senp2 regulates MCD-induced liver fibrosis, with a focus on vascular remodeling. Liver-specific Senp2 knockout mice and wild-type littermates were fed an MCD diet to establish fibrosis. Liver injury, fibrosis, inflammation, and angiogenesis were assessed. Hepatic Senp2 deficiency markedly attenuated MCD-induced liver injury, fibrosis, and inflammation. Notably, Senp2 loss triggered a distinct hepatic vascular remodeling pattern: it promoted portal angiogenesis while suppressing hepatic sinusoidal capillarization, as evidenced by altered Cd31 expression and vascular architecture. Mechanistically, Senp2 ablation significantly reduced leukocyte cell-derived chemotaxin 2 (LEC2) expression and secretion, alongside downregulation of both active non-phospho-β-catenin and total β-catenin. In the MCD-induced fibrosis model, hepatic Senp2 drives pathological vascular remodeling through a β-catenin/Lect2 axis. Loss of Senp2 restrains this pathway, rebalances hepatic angiogenesis, and ultimately mitigates fibrosis progression. This reveals a nutrition-specific, pro-fibrotic mechanism of Senp2 centered on vascular regulation, highlighting a potential therapeutic target for non-metabolic fibrotic liver diseases.