Exploring hepatic stellate cell-driven fibrosis: therapeutic advances and future perspectives

Abstract

Background and purpose: Liver fibrosis, a progressive liver disease arising from viral or metabolic causes, poses a major global health challenge due to its potential progression to cirrhosis and hepatocellular carcinoma. Due to the complex aetiology and epidemiology of liver fibrosis, most therapies fail in the clinic, and very few drugs have been approved by the US FDA.

Approach: This review highlights the pathophysiological features of liver fibrosis, with a focus on novel targets in hepatic stellate cells (HSCs), key players in the fibrogenesis process, to develop successful therapeutic approaches using both pharmacological agents and active targeting strategies. The review also examines current therapeutic strategies targeting liver fibrosis, both in preclinical lab setups and clinical trials. Furthermore, various receptors involved in HSC-mediated liver fibrosis and active drug delivery targeting strategies are reviewed to enhance therapeutic outcomes. This article also integrates existing knowledge to identify research gaps and guide future investigations and clinical translation in liver fibrosis treatment. In addition, novel pathways pertaining to liver fibrosis, such as the RSPO3-LGR4/5-β-catenin cascade, the CD47/YAP/TEAD4 signalling axis, and HAb18G/CD147, are briefly elaborated in the context of therapeutic approaches for arresting HSC activation. Single-cell RNA sequencing of HSCs is presented to provide a clearer picture of liver fibrosis.

Conclusion: The review highlights critical research gaps in liver fibrosis therapy and promising active targeting strategies and pharmacological interventions to improve therapeutic outcomes. Overall, this review provides a robust foundation for scientists and clinicians to advance active targeting of the disease pathology and to develop new pharmaceutical formulations that are pharmacologically safer and more efficacious.

Keywords: Retinoid receptors; active targeting; clinical trials; liposomes; non-alcoholic fatty liver disease; resmetirom.

Figure 1.

Pathophysiology of hepatic stellate cells. Several dramatic changes occurred during the development of liver fibrosis at cellular level. Liver fibrosis is incurred by several factors, including drugs, schistosomes, SIBO, HCV & HBV, and alcohol followed by HSC activation. Regular injury fosters a chronic liver disease. In activated HSC cells, collagen and extracellular matrix accumulation, vitamin A is lost, and oxidative stress occurs. Overall, cells including Macrophages, Kupffer cells, platelets, B cells, and natural killer cells are involved in the activation of HSC

Figure 2.

Mechanisms of action of thyroid hormones and resmetirom in regulation of hepatocyte lipid metabolism., Thyroxine (T4), Iodothyronine deiodinase 1 (DIO1) Triiodothyronine (T3), Nuclear thyroid receptor β (THR-β), Retinoid X receptor (RXR) Carnitine palmitoyltransferase I (CPT1), Mitochondrial fatty acid oxidation (FAO), and Sterol regulatory element binding transcription factor 1 (SREBF1) Iodothyronine deiodinase 1 (DIO3), reverse T3 (rT3). Modified from [57], Creative Commons CC BY

Figure 3.

a - targets of belapectin for alleviation of fibrosis; b - Molecular mechanisms of action of pirfenidone. It affects signalling pathways such as the Smad pathway, which is downstream of TGF-β, leading to a decrease of fibrogenic activity. Consequently, it inhibits fibroblast proliferation and increases fibroblast apoptosis

Figure 4.

Major drug delivery systems with active targeting agents use for the therapy of liver fibrosis (Created in BioRender. Awasthi, R. (2025) https://BioRender.com/obrtwsc)