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Abstract While ultrasonography effectively diagnoses Hashimoto’s thyroiditis (HT), exploring its transcriptomic landscape could reveal valuable insights into disease mechanisms. This study aimed to identify HT-associated RNA signatures and investigate their potential for enhanced molecular characterization. Samples comprising 31 HT patients and 30 healthy controls underwent RNA sequencing of peripheral blood. Differential expression analysis identified transcriptomic features, which were integrated using multi-omics factor analysis. Pathway enrichment, co-expression, and regulatory network analyses were performed. A novel machine-learning model was developed for HT molecular characterization using stacking techniques. HT patients exhibited increased thyroid volume, elevated tissue hardness, and higher antibody levels despite being in the early subclinical stage. Analysis identified 79 HT-associated transcriptomic features (3 mRNA, 6 miRNA, 64 lncRNA, 6 circRNA). Co-expression (77 nodes, 266 edges) and regulatory (18 nodes, 45 edges) networks revealed significant hub genes and modules associated with HT. Enrichment analysis highlighted dysregulation in immune system, cell adhesion and migration, and RNA/protein regulation pathways. The novel stacking-model achieved 95% accuracy and 97% AUC for HT molecular characterization. This study demonstrates the value of transcriptome analysis in uncovering HT-associated signatures, providing insights into molecular changes and potentially guiding future research on disease mechanisms and therapeutic strategies.