Exercise suppresses IP6K3 to modulate BCAA metabolism and ferroptosis in MASLD

Area of Science:

• Hepatology and metabolic research
• Molecular mechanisms of liver disease
• Exercise physiology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with branched-chain amino acid (BCAA) dysmetabolism and ferroptosis.
• The protective role of exercise in MASLD is established, but the underlying molecular mechanisms require elucidation.

Purpose of the Study:

• To identify key regulators of MASLD and elucidate the mechanisms behind exercise-induced protection.
• To investigate the role of inositol hexakisphosphate kinase 3 (IP6K3) in MASLD pathogenesis and its modulation by exercise.

Main Methods:

• Integrated bioinformatic analyses of public datasets and analysis of human and mouse liver samples.
• Functional assessment of IP6K3 using hepatocyte-specific gene deletion, exercise intervention, single-cell RNA sequencing (scRNA-seq), and molecular assays.
• Exploration of molecular interactions using overexpression/knockdown studies, mass spectrometry, and co-immunoprecipitation.

Main Results:

• Hepatic IP6K3 expression is upregulated in MASLD and reduced by exercise in mice.
• Hepatocyte-specific deletion of IP6K3 confers resistance to MASLD, linked to enhanced BCAA degradation and ferroptosis inhibition.
• IP6K3 interacts with HNRNPK, influencing BCAT2 mRNA stability, BCAA catabolism, and ferroptosis prevention.

Conclusions:

• IP6K3 is identified as a critical mediator of exercise-induced protection against MASLD.
• Targeting IP6K3 may offer a novel pharmacological strategy for MASLD intervention.