Integrated Plasma Proteomics and Functional Analyses Reveal Hepatic CDHR2 as a Potential Therapeutic Target in MASLD

Area of Science:

• Hepatology and Metabolic Diseases
• Genetics and Proteomics
• Molecular Biology

Background:

• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition with limited therapeutic options.
• Identifying novel molecular targets is crucial for developing effective treatments for MASLD.

Purpose of the Study:

• To integrate multi-omics data for identifying and functionally validating protein targets in MASLD.
• To investigate the causal role of candidate proteins in MASLD and liver cirrhosis.

Main Methods:

• Analysis of UK Biobank data including imaging-derived cT1 and plasma proteomic data.
• Two-sample Mendelian randomization (MR) to assess causal relationships between proteins and MASLD/cirrhosis.
• In vitro functional studies using hepatocyte models to evaluate CDHR2's role in lipid accumulation and signaling.

Main Results:

• 36 proteins associated with cT1 in fatty liver patients were identified.
• Cadherin-Related Family Member 2 (CDHR2) showed a causal association with increased risk of MASLD and liver cirrhosis.
• CDHR2 was upregulated in MASLD hepatocytes, and its knockdown reduced adipogenesis and enhanced antioxidant response in vitro.

Conclusions:

• CDHR2 is identified as a novel regulator in the development and progression of MASLD.
• CDHR2 represents a potential therapeutic target for MASLD and related liver conditions.