Present and Future Perspectives in the Treatment of Liver Fibrosis

Abstract

Background/objectives: Liver fibrosis is a progressive consequence of chronic liver injury that can evolve into cirrhosis, liver failure, or hepatocellular carcinoma, representing a major global health burden. Fibrogenesis is driven by hepatic stellate cell (HSC) activation, excessive extracellular matrix deposition, and structural disruption of liver tissue, with transforming growth factor-β (TGF-β) signaling and inflammatory mediators as central pathways. Current therapies primarily target the underlying causes, which may halt disease progression but rarely reverse established fibrosis. This review aims to outline current and emerging therapeutic strategies for liver fibrosis, informing both clinical practice and future research directions.

Methods: A narrative synthesis of preclinical and clinical evidence was conducted, focusing on pharmacological interventions, microbiota-directed strategies, and innovative modalities under investigation for antifibrotic activity.

Results: Bile acids, including ursodeoxycholic acid and derivatives, modulate HSC activity and autophagy. Farnesoid X receptor (FXR) agonists, such as obeticholic acid, reduce fibrosis but are limited by adverse effects. Fatty acid synthase inhibitors, exemplified by denifanstat, show promise in metabolic dysfunction-associated steatohepatitis (MASH). Additional strategies include renin-angiotensin system inhibitors, omega-3 fatty acids, and agents targeting the gut-liver axis. Microbiota-directed interventions-probiotics, prebiotics, symbiotics, antibiotics (e.g., rifaximin), and fecal microbiota transplantation-are emerging as potential modulators of barrier integrity, inflammation, and fibrogenesis, though larger clinical trials are required. Reliable non-invasive biomarkers and innovative trial designs, including adaptive platforms, are essential to improve patient selection and efficiently evaluate multiple agents and combinations.

Conclusions: Novel modalities such as immunotherapy, gene editing, and multi-targeted therapies hold additional potential for fibrosis reversal. Continued translational efforts are critical to establish safe, effective, and accessible treatments for patients with liver fibrosis.

Keywords: farnesoid X receptor (FXR) agonists; gut–liver axis; hepatic stellate cells (HSC); liver fibrosis; transforming growth factor-β (TGF-β).

Figure 1

Schematic representation of the main cellular and molecular mechanisms involved in liver fibrosis. Chronic liver injury activates hepatocytes and Kupffer cells, which release inflammatory and fibrogenic mediators such as TNF-α, IL-1β, and TGF-β1. These factors induce hepatic stellate cell activation and extracellular matrix deposition. Signals from platelet-derived growth factor (PDGF), oxidative stress, and gut-derived endotoxins such as lipopolysaccharide (LPS) further promote fibrogenesis. Mechanotransduction pathways including Hippo/YAP/TAZ and RhoA/ROCK are also involved in maintaining the activated state of stellate cells in response to matrix stiffness. Components of the gut–liver axis, particularly microbiota-derived signals, contribute to immune dysregulation and hepatic inflammation.

Figure 2

Chemical structure of selected antifibrotic agents discussed *. * Biologic agents and peptides (e.g., GLP-1 receptor agonists and FGF21 analogs) are not represented due to their large molecular size and structural complexity, which limit their inclusion in standard chemical structure formats.