In advanced chronic liver disease (ACLD), de-regulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed at characterizing the effects of the pan-peroxisome proliferator-activated receptors (pan-PPAR) agonist lanifibranor in two pre-clinical models of ACLD, as well as in liver cells from patients with ACLD.Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100mg/kg/day, po) or vehicle for 14 days (n=12/group). PPAR expression, systemic and hepatic hemodynamics, presence of ascites, liver sinusoidal endothelial cells (LSEC) phenotype, hepatic stellate cells (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from livers from cirrhotic patients and their phenotype was evaluated after treatment with lanifibranor or vehicle.TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure than vehicle-treated animals (-15%) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved phenotype of LSEC and HSC, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%). These findings were confirmed in the cBDL rat model, as well as in human liver cells from cirrhotic patients, which exhibited a phenotypic improvement upon treatment with lanifibranor.This study demonstrates that lanifibranor exerts clear beneficial effects in pre-clinical models of decompensated cirrhosis, which lead to amelioration in fibrosis and portal hypertension. Our results in human hepatic cells isolated from cirrhotic patients further encourage its clinical evaluation for the treatment of ACLD.