In advanced chronic liver disease (ACLD), deregulated 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 to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical 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 (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

Chronic liver disease constitutes a growing public health issue worldwide, with no safe and effective enough treatment clinical scenarios. The present review provides an overview of the current knowledge regarding advanced chronic liver disease (ACLD), focusing on the major contributors of its pathophysiology: inflammation, oxidative stress, fibrosis and portal hypertension. We present the benefits of supplementation with docosahexaenoic acid triglycerides (TG-DHA) in other health areas as demonstrated experimentally, and explore its potential as a novel nutraceutical approach for the treatment of ACLD and portal hypertension based on published pre-clinical data.

Inflammation and oxidative stress play a key role in the pathophysiology of advanced chronic liver disease (ACLD) and portal hypertension (PH). Considering the current lack of effective treatments, we evaluated an anti-inflammatory and antioxidant nutraceutical rich in docosahexaenoic acid (DHA) as a possible therapy for ACLD. We investigated the effects of two-week DHA supplementation (500 mg/kg) on hepatic fatty acids, PH, oxidative stress, inflammation, and hepatic stellate cell (HSC) phenotype in rats with ACLD. Additionally, the effects of DHA were evaluated in murine macrophages and human HSC. In contrast to vehicle-treated animals, cirrhotic rats receiving DHA reestablished a healthy hepatic fatty acid profile, which was associated with an improvement in PH. The mechanisms underlying this hemodynamic improvement included a reduction in oxidative stress and inflammation, as well as a marked HSC deactivation, confirmed in human HSC. Experiments with cultured macrophages showed that treatment with DHA protects against pro-inflammatory insults. The present preclinical study demonstrates that a nutraceutical rich in DHA significantly improves PH in chronic liver disease mainly by suppressing inflammation and oxidative stress-driven HSC activation, encouraging its evaluation as a new treatment for PH and cirrhosis.

Background and Aims: Portal vein thrombosis (PVT) is a frequent complication of cirrhosis, yet its pathophysiology remains elusive. Unlike thrombosis in other vascular beds, anticoagulation often fails to completely recanalize PVT, highlighting the need for greater mechanistic insight and alternative therapeutic approaches. Our study aimed to characterize the structural and cellular changes in the portal venous vascular bed to identify novel physiologically driven therapeutic targets. Approach and Results: Portal vein tissue specimens from explanted livers of patients with cirrhosis with and without PVT and from liver donors were histologically analyzed. PVT is associated with a remarkable eccentric thickening of the tunica intima due to accumulation of extracellular material and tunica intima increased cellularity. Transcriptomic analysis of human portal vein endothelial cells (PVEC) from patients with PVT identified the endothelial-to-mesenchymal transition (EndMT) pathway upregulated in PVECs from patients with PVT. In silico drug repurposing analysis identified statins as potential agents targeting these alterations. In vitro treatment with statins attenuated hallmarks of EndMT in primary human PVECs. Conclusions: In cirrhosis, the portal vein endothelium undergoes maladaptive remodeling marked by eccentric intimal hyperplasia, driven by ECM accumulation and infiltration of inflammatory and myofibroblast-like cells. This process narrows the lumen and may promote PVT. EndMT plays a key role in this transformation and emerges as a novel and promising therapeutic target. Notably, statins can attenuate EndMT, highlighting its potential in PVT treatment.

Steatotic liver disease can lead to the development of metabolic dysfunction-associated steatohepatitis (MASH), the prevalence of which is rapidly increasing, intensifying the need to find an effective treatment. GTX-11 is a first-in-class drug with anti-inflammatory and antifibrotic properties mediated by the modulation of the transforming growth factor beta pathway. The present study evaluated the effects of GTX-11 on hepatic hemodynamics and liver fibrosis, as well as its underlying mechanisms, in a preclinical model of MASH, and in human precision-cut liver slices (hPCLS). Male Wistar MASH rats received GTX-11 (1 and 10 mg/kg/day) or vehicle, for 14 days (n = 15/group). In vivo systemic and hepatic hemodynamics, fibrosis, biochemical parameters, and hepatic cells phenotype were analyzed. hPCLS were obtained from human hepatic resections and incubated with the active metabolite of GTX-11 (GTX-11m) (1 μM or 10 μM) or vehicle for 24 h. Gene expression changes were evaluated by RNA sequencing and gene deconvolution analysis was performed (n = 6/group). MASH rats receiving GTX-11 showed a significant dose-dependent reduction in portal pressure compared with the vehicle (-8.4% p = 0.05 and -11.7% p <0.01 for 1 and 10 mg/kg, respectively), associated with lower hepatic fibrosis at 10 mg/kg (-28%, p 3–6% of the world’s population, and this number continues to increase. Despite its high prevalence, there is currently no specific, generally effective, and safe treatment for the disease. This study demonstrates, for the first time, the therapeutic potential of GTX-11 in treating fibrosis and portal hypertension associated with MASH by deactivating hepatic stellate cells and enhancing endothelial phenotype. These findings highlight GTX-11 as a promising candidate for future therapeutic strategies aimed at reversing liver fibrosis and improving patient outcomes in MASH.