Discovery of the Insecticide Chlorantraniliprole as a Thyroid Hormone Receptor β Antagonist Reinforcing Thyroid-Liver Metabolic Disruption to Promote Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide with increasing evidence implicating environmental factors in its development. Although thyroid hormone receptor β (TRβ) plays a pivotal role in MASLD progression, few TRβ disruptors are known due to the receptor’s high structural specificity for ligands. In this study, we established a TRβ protein-affinity guided nontargeted identification method and applied it to water samples from the Yangtze and Yellow Rivers, identifying 11 novel TRβ antagonists (IC₅₀: 5.58–80.00 μM). Among them, the insecticide chlorantraniliprole (CAP) emerged as the most potent TRβ antagonist with the highest bioanalytical equivalent concentration, and its effective serum concentrations in mice were even lower than some reported human serum levels. Mechanically, CAP suppressed triiodothyronine (T3)-TRβ-mediated triglyceride assembly and cholesterol metabolism, leading to significant lipid accumulation in liver. Simultaneously, CAP interfered with thyroid TRβ signaling and inhibited thyroid hormone synthesis, resulting in systemic thyroid hormone deficiency that further exacerbated hepatic TRβ antagonism. This reciprocal disruption of the liver-thyroid crosstalk reinforced metabolic imbalance and promoted MASLD development in mice. These preclinical and environmental findings establish TRβ as a plausible molecular target of environmental exposures, warranting human studies to validate the clinical relevance of CAP.