Targeting THR-β for MASLD Treatment: Current Progression and Emerging Prospects.

Area of Science:

• Hepatology
• Endocrinology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a significant global health challenge with limited effective treatments.
• Thyroid hormone receptor-beta (THR-β) is crucial for liver lipid metabolism, inflammation, and fibrosis, making it a key therapeutic target.
• Previous THR-β agonists faced limitations due to systemic side effects and lack of selectivity.

Purpose of the Study:

• To review MASLD pathogenesis and current therapeutic strategies.
• To elucidate the role and structure of THR-β in liver health.
• To evaluate existing and novel THR-β agonists for MASLD treatment.

Main Methods:

• Review of scientific literature on MASLD, THR-β biology, and pharmacotherapy.
• Analysis of clinical data and preclinical studies of THR-β agonists.
• Examination of advancements in selective THR-β agonist development.

Main Results:

• Highly selective THR-β agonists with enhanced potency have been developed through medicinal chemistry.
• Resmetirom (MGL-3196), a liver-targeted THR-β agonist, has received FDA approval, marking a significant advancement.
• Selective agonists demonstrate improved therapeutic potential with reduced off-target effects.

Conclusions:

• Targeting THR-β represents a breakthrough in MASLD pharmacotherapy.
• Selective THR-β agonists offer a promising therapeutic avenue for managing MASLD.
• Future research should focus on optimizing THR-β-targeted therapies for improved patient outcomes.