Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated...

Area of Science:

• Hepatology
• Molecular Biology
• Genomics

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent global liver condition.
• Lifestyle modification is the primary management strategy for MASLD.
• Persistent molecular signals in MASLD post-remission remain poorly understood.

Purpose of the Study:

• To investigate persistent transcriptomic changes in the liver following MASLD reversal.
• To identify molecular mechanisms contributing to potential MASLD relapse.

Main Methods:

• Mice were fed a Western diet (WD) or chow diet (CD), or underwent diet reversal from WD to CD.
• Liver RNA sequencing was performed to analyze transcriptomic profiles.
• Data from P53-knockout mice and human MASLD samples were integrated.

Main Results:

• Dietary reversal of WD-induced MASLD revealed persistent activation of the DNA damage response (DDR) and P53.
• Elevated P53 correlated with hepatocyte ballooning, suggesting a role in apoptosis.
• P53 knockout reduced apoptosis signaling; P53 may upregulate apoptosis-enhancing nuclease (AEN).

Conclusions:

• The P53-AEN-apoptosis axis and DDR signaling are upregulated during and after WD exposure in the liver.
• These findings offer insights into MASLD relapse mechanisms.
• DDR signaling presents a potential therapeutic target for preventing MASLD recurrence.