Tear Metabolomics in Thyroid Eye Disease: Molecular Signatures, Disease Activity, and Therapeutic Implications

Thyroid eye disease (TED) is a complex autoimmune orbital disease where clinical assessment tools, such as the Clinical Activity Score, often fail to capture the underlying molecular transitions between active inflammation and permanent fibrosis. As the field moves toward precision medicine, tear film metabolomics has emerged as a powerful, noninvasive source of biomarkers that can decode the orbital microenvironment. This review synthesizes current evidence on the metabolic signatures of TED, highlighting the shift from traditional protein biomarkers to small-molecule metabolites, including lipids, amino acids, and oxidative stress products. The current literature provides evidence that alterations in amino acid metabolism, polyamine synthesis, acylcarnitine profiles, and other markers of oxidative stress indicate disease activity in TED. We explore how liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have identified key dysregulated pathways—most notably in the ornithine-polyamine axis, with an increased putrescine-to-ornithine ratio correlating best with inflammatory activity. By bridging the gap between systemic thyroid dysfunction and localized ocular manifestations, tear metabolomics offers a promising noninvasive approach for biomarker development, disease stratification, and therapeutic decision-making in thyroid eye disease.