Metabolic dysfunction-associated steatohepatitis reduces hepatic H₂S-producing enzymes altering persulfidome...

Area of Science:

• Biochemistry
• Hepatology
• Redox Biology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) involves hepatic inflammation and oxidative stress.
• Cysteine persulfidation (PSSH), a modification by hydrogen sulfide (H2S), is crucial for redox regulation.
• The role of PSSH in MASH pathogenesis is not well understood.

Purpose of the Study:

• To investigate the role and alterations of PSSH in MASH.
• To identify specific proteins affected by PSSH dysregulation in MASH.
• To explore the therapeutic potential of PSSH in MASH.

Main Methods:

• Analysis of H2S-producing enzymes in human and mouse MASH models.
• Dimedone-switch mass spectrometry to profile PSSH on proteins.
• Comparison of PSSH levels across distinct stages of obesity-associated liver disease.

Main Results:

• Downregulation of H2S-producing enzymes and reduced global PSSH levels in MASH livers.
• Identification of dysregulated PSSH on specific proteins, including phosphatases and redox regulators.
• Increased PSSH on certain proteins in advanced MASH stages, suggesting an adaptive response.

Conclusions:

• Impaired H2S production disrupts protective PSSH networks in MASH.
• Selective PSSH on redox-sensitive proteins may be a compensatory mechanism.
• Persulfidation holds therapeutic potential for restoring redox balance in MASH.