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

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a critical global public health challenge, with limited therapeutic options underscoring the necessity for innovative therapies. Thyroid hormone receptor-β (THR-β), the predominant THR isoforms in the liver, plays a pivotal role in regulating lipid homeostasis, inflammation, and hepatic fibrosis, positioning it as a compelling therapeutic target. Although early THR-β agonists have demonstrated potential, their clinical application was restricted by systemic side effects and poor THR-β selectivity. Advances in medical chemistry have now developed highly selective THR-β with improved potency. The recent FDA approval of Resmetirom (MGL-3196), a liver-targeted THR-β agonist, represents a transformative milestone in MASLD pharmacotherapy. This perspective examines MASLD pathogenesis and current therapeutic landscape, elucidates the biological functions and structural features of THR-β, and critically evaluates existing and emerging THR-β agonists. Additionally, we highlight breakthroughs in selective THR-β agonists development and discuss future directions for optimizing THR-β-targeted therapies.