{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T17:00:41Z","timestamp":1758042041565,"version":"3.44.0"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Differentiation between benign and malignant thyroid nodules has been a challenge in clinical practice. We aim to explore a novel biomarker to determine the malignancy of thyroid nodules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the discovery study, 32 tissue samples from benign thyroid nodule (BTN) and thyroid cancer (TC) patients were analyzed by Methylation 850K array and RNA-Sequencing. TC associated <jats:italic>FABP3<\/jats:italic> methylation was further verified by mass spectrometry in two independent studies (221 BTN vs. 222 TC in Validation I and 191 BTN vs. 256 TC in Validation II). Logistic regression analysis and non-parametric tests were used for the analysis between groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Altered and inversely correlated methylation and expression in the <jats:italic>FABP3<\/jats:italic> gene in TC was found in the discovery study (<jats:italic>P<\/jats:italic> = 2.90E-05 for the methylation and <jats:italic>P<\/jats:italic> = 0.040 for the expression), and verified in the two validation studies (<jats:italic>P<\/jats:italic> values range from 0.012 to 6.30E - 10-12). <jats:italic>FABP3<\/jats:italic> methylation could sufficiently differentiate TC from BTN (AUC = 0.77), and could be further improved when combined with the BRAF<jats:sup>V600E<\/jats:sup> mutations (AUC = 0.87). The association between <jats:italic>FABP3<\/jats:italic> hypomethylation and TC was enhanced in women, in patients with younger age, with larger tumor size and with lower FT3. <jats:italic>FABP3<\/jats:italic> methylation was varied in BTN and TC subtypes, with the highest level in adenoma and the lowest in anaplastic thyroid cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study suggested that altered <jats:italic>FABP3<\/jats:italic> methylation in tissue samples as a potential biomarker to distinguish malignant and benign thyroid nodules, and might be helpful for the pathological classification of TC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1630001","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T13:51:15Z","timestamp":1757598675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FABP3 methylation as a novel biomarker for 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