Complex I Modulator BI4500 Reduces MASH by Limiting Oxidative Stress and Reprogramming Lipid Metabolism via AMPK in...

Area of Science:

• Hepatology
• Mitochondrial Biology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) involves mitochondrial dysfunction, oxidative stress, and inflammation, driving progression to MASH and HCC.
• Mitochondrial Complex I is a key source of reactive oxygen species (ROS), particularly in dysregulated metabolism.
• Metformin's Complex I inhibition reduces ROS and activates AMPK, suggesting similar modulators could be therapeutic.

Purpose of the Study:

• To evaluate a novel Complex I Modulator (CIM, BI4500) for its potential to reduce oxidative stress, inflammation, lipid accumulation, and fibrosis in a rat model of MASH.
• To investigate CIM's effects on mitochondrial function, metabolic reprogramming, and key molecular pathways involved in MASH pathogenesis.

Main Methods:

• Rats were fed a methionine- and choline-deficient (MCD) diet for six weeks, with CIM or vehicle treatment initiated at week four.
• Liver tissues underwent histological, biochemical, and molecular analyses to assess lipid droplets, inflammation, collagen, oxidative stress markers, and gene/protein expression.
• Key pathways evaluated included oxidative stress, lipid metabolism (PPAR-α, SREBP-1c), and fibrosis markers.

Main Results:

• CIM treatment significantly decreased oxidative stress markers (ROS, lipid peroxidation, nitrogen species) and promoted AMPK activation.
• Metabolic reprogramming occurred, characterized by increased PPAR-α pathway activity and decreased SREBP-1c-driven lipogenesis.
• Fibrosis progression was halted, evidenced by reduced collagen deposition and fibrosis markers.

Conclusions:

• Complex I modulation with CIM effectively attenuated key pathological features of MASH in a preclinical model.
• CIM demonstrated potential to counteract MASLD progression by addressing mitochondrial dysfunction, oxidative stress, and inflammation.
• Targeting Mitochondrial Complex I represents a promising therapeutic strategy for MASLD and MASH.