Targeting the Wnt signaling pathway: the challenge of reducing scarring without affecting repair

ABSTRACT

Introduction: Globally, deaths from liver disease are increasing and for most patients there are few curative options. Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking. Recent work has shown that Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.

Areas covered: This article seeks to shed light on the dualistic role of Wnt signaling in liver regeneration following injury and how Wnt signaling can regulate scar formation. It also discusses how Wnt signaling cooperates with other classical fibrogenic signaling cascades, such as TGFβ signaling. Finally, the article examines recent advances in the development of Wnt signaling pathway inhibitors and asks whether repurposing these agents as anti-fibrotic therapies is a realistic option.

Expert opinion: The understanding of Wnt signaling in liver regeneration and fibrosis is in its infancy and whilst new generations of Wnt pathway inhibitors have shown anti-fibrotic effects, further research is necessary to enhance our understanding of the Wnt-landscape in different patterns of liver disease. This will accelerate the development of more specific Wnt inhibitor-based anti-fibrotics

KEYWORDS:

• Wnt signaling
• liver fibrosis
• NAFLD
• nonalcoholic fatty liver disease
• liver disease
• wnt inhibition
• anti-fibrotics
• TGF-β

Article highlights

• Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking

• Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.

• Wnt signaling is important for epithelial regeneration and for scarring.

• Wnt signaling interacts with classical scarring signals in the liver, such as TGFb signaling.

• Therapeutic modulation of Wnt signaling can be used to reduce liver fibrosis experimentally; however, a more in-depth understanding is needed prior to translation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. All figures were created with BioRender.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

LB is funded by core funding provided to the MRC Human Genetics Unit, by the Medical Research Council.