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

## TL;DR

This review explores new ways to treat liver fibrosis by focusing on hepatic stellate cells and potential drug targets.

## Contribution

The paper introduces novel therapeutic targets and strategies for liver fibrosis, including specific signaling pathways and active drug delivery methods.

## Key findings

- Novel pathways like RSPO3-LGR4/5-β-catenin and CD47/YAP/TEAD4 are identified as potential therapeutic targets.
- Active targeting strategies and single-cell RNA sequencing of HSCs offer new insights into liver fibrosis treatment.
- Current therapies often fail, highlighting the need for safer and more effective pharmacological interventions.

## Abstract

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.

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.

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.