Linoleic acid reduces sodium-iodide symporter by inhibiting endoplasmic reticulum stress in papillary thyroid...

Novel biomarkers are imperative for predicting radioactive iodine (RAI) avidity in metastatic lesions of differentiated thyroid carcinoma, and mechanisms regulating RAI uptake remain incompletely understood. This study aimed to identify distinct serum metabolic profiles in papillary thyroid carcinoma (PTC) patients with non-131I-avid disease and elucidate underlying molecular mechanisms. Serum samples from 94 PTC patients were analyzed using gas chromatography-time-of-flight mass spectrometry. Patients were stratified into the non-131I-avid pulmonary metastases group (n = 30), the 131I-avid pulmonary metastases group (n = 31), and the remnant ablation group (n = 33). Principal component analysis and orthogonal partial least squares-discriminant analysis was employed for classification and biomarker identification. Differential metabolites were visualized via heatmap and evaluated for diagnostic potential using receiver operating characteristic curve analysis. Pathway enrichment analysis utilized the KEGG database. Sixty metabolites were significantly dysregulated between non-131I-avid and 131I-avid groups: 54 elevated (fold change (FC) range: 1.17-4.81) and 6 reduced (FC range: 0.31-0.82) in the non-131I-avid cohort. Ten metabolites demonstrated a high predictive power for non-131I-avid pulmonary metastatic PTC (AUC > 0.9; P < 0.001). Pathway analysis identified linoleic acid (LA) metabolism as the most significantly altered pathway (impact factor = 1.0). Mechanistically, LA competitively inhibited the binding of the endoplasmic reticulum (ER) stress-responsive transcription factor ATF4 to the sodium-iodide symporter (NIS) promoter, suppressing NIS transcription. Serum metabolomic profiling effectively discriminates PTC patients with pulmonary metastases based on 131I avidity. Our findings demonstrate that LA attenuates NIS expression by inhibiting ER stress-mediated ATF4 activation in PTC. This work provides novel mechanistic insights into non-131I-avid metastatic PTC development and identifies potential diagnostic biomarkers and therapeutic targets.