Hepatocyte DDIT4 aggravates MASH progression through GPX4-mediated ferroptosis.

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options.
• The role of ferroptosis in MASH pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the role of DNA damage-inducible transcript 4 (DDIT4) in ferroptosis and MASH progression.
• To identify potential therapeutic targets for MASH.

Main Methods:

• Analysis of MASH mouse models and patient data from public databases.
• Assessment of DDIT4 expression in MASH.
• Functional studies using hepatocyte-specific DDIT4 overexpression and knockout mouse models.
• RNA-sequencing, immunoprecipitation-mass spectrometry (IP-MS), and molecular docking to identify DDIT4 interactions and potential drug targets.

Main Results:

• DDIT4 levels were significantly elevated in MASH, correlating with disease severity.
• DDIT4 overexpression aggravated MASH and ferroptosis, while DDIT4 deletion alleviated these conditions.
• DDIT4 reduced glutathione peroxidase 4 (GPX4) via mTORC1, inhibited mitochondrial GPX4 translocation, and promoted ferroptosis.
• Quercetagetin was identified as a DDIT4-targeting compound that ameliorated MASH in mice.

Conclusions:

• The DDIT4-GPX4-ferroptosis pathway is a key regulator of MASH progression.
• DDIT4 represents a promising therapeutic target for MASH treatment.