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Although thyroid hormone receptor \u03b2 (TR\u03b2) plays a pivotal role in MASLD progression, few TR\u03b2 disruptors are known due to the receptor\u2019s high structural specificity for ligands. In this study, we established a TR\u03b2 protein-affinity guided nontargeted identification method and applied it to water samples from the Yangtze and Yellow Rivers, identifying 11 novel TR\u03b2 antagonists (IC50: 5.58\u201380.00 \u03bcM). Among them, the insecticide chlorantraniliprole (CAP) emerged as the most potent TR\u03b2 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)-TR\u03b2-mediated triglyceride assembly and cholesterol metabolism, leading to significant lipid accumulation in liver. Simultaneously, CAP interfered with thyroid TR\u03b2 signaling and inhibited thyroid hormone synthesis, resulting in systemic thyroid hormone deficiency that further exacerbated hepatic TR\u03b2 antagonism. This reciprocal disruption of the liver-thyroid crosstalk reinforced metabolic imbalance and promoted MASLD development in mice. These preclinical and environmental findings establish TR\u03b2 as a plausible molecular target of environmental exposures, warranting human studies to validate the clinical relevance of CAP.<\/jats:p>","DOI":"10.1021\/acs.est.5c07061","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:47:36Z","timestamp":1760118456000},"page":"21872-21884","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of the\nInsecticide Chlorantraniliprole as\na Thyroid Hormone Receptor \u03b2 Antagonist Reinforcing Thyroid-Liver\nMetabolic Disruption to Promote Metabolic Dysfunction-Associated Steatotic\nLiver Disease"],"prefix":"10.1021","volume":"59","author":[{"given":"Ling","family":"Jiao","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailin","family":"Shang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehua","family":"Liu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Li","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqi","family":"Sun","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6025-338X","authenticated-orcid":true,"given":"Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"China National Center for Food Safety Risk Assessment , , ,","place":["Beijing, China, 100021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1965-7494","authenticated-orcid":true,"given":"Jianying","family":"Hu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1312-6254","authenticated-orcid":true,"given":"Yi","family":"Wan","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"issue":"1","key":"2026081812155801400_cit1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s12902-022-00980-1","article-title":"Non-alcoholic fatty liver disease (NAFLD): a review\nof pathophysiology, clinical management and effects of weight loss","volume":"22","author":"Pouwels","year":"2022","journal-title":"BMC Endocr. 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Res."},{"key":"2026081812155801400_cit46","volume-title":"Application of Chlorantraniliprole\nto Non-Commercial\nTurf for Japanese Beetle Treatment","author":"Sutherland-Ashley","year":"2020"},{"issue":"24","key":"2026081812155801400_cit47","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1080\/15287394.2024.2407479","article-title":"Rhinella arenarumEffects\nof anthranilic diamide insecticides\non metamorphosis in the common toad (Hensel, 1867) at concentrations\nfound in aquatic environments","volume":"87","author":"Pen\u0303a","year":"2024","journal-title":"J. Toxicol. Environ.\nHealth A"},{"key":"2026081812155801400_cit48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclepro.2021.129897","article-title":"Spatio-temporal\nanalysis of water quality for pesticides and other agricultural pollutants\nin Deduru Oya river basin of Sri Lanka","volume":"330","author":"Jayasiri","year":"2022","journal-title":"J. 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