Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

Area of Science:

• Hepatology and molecular biology research.

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are prevalent chronic liver conditions with significant health risks.
• The underlying molecular mechanisms driving MASLD and MASH development and progression remain incompletely understood.

Approach:

• Conducted an extensive meta-analysis of 10 hepatic gene expression datasets (1,058 samples) using RNA-sequencing and microarray data.
• Employed a random-effects meta-analysis model to compare over 12,000 genes across MASLD, MASH, and normal liver samples.
• Integrated gene expression findings with genome-wide association studies and coexpression network analysis.

Key Points:

• Identified 685 differentially expressed genes in MASLD vs. normal liver, 1,870 in MASH vs. normal liver, and 3,284 in MASLD vs. MASH.
• Discovered two functionally relevant coexpression modules, one driven by SMOC2, ITGBL1, LOXL1, MGP, and SOD3.
• Identified a novel coexpression module associated with MASLD and MASH progression, driven by TAT, HGD, and SLC25A15.

Conclusions:

• This meta-analysis provides a comprehensive and robust overview of hepatic gene expression alterations in MASLD and MASH.
• Identified novel key molecular drivers, including TAT, HGD, and SLC25A15, implicated in the progression of these liver conditions.