Lifestyle-associated hyperglycemia and aberrant TSH glycoforms in aggressive thyroid carcinoma: glycosylation-mediated mechanisms in treatment resistance hyperglycemia, TSH glycoforms & thyroid cancer

This review examines the critical intersection between lifestyle-associated hyperglycemia and aggressive thyroid carcinoma, with a particular focus on the role of aberrant thyroid-stimulating hormone (TSH) glycosylation. Chronic hyperglycemia, a characteristic of metabolic disorders such as type 2 diabetes, contributes to a pro-oxidative and pro-inflammatory tumor microenvironment. We propose that this metabolic stress enhances the hexosamine biosynthetic pathway, which may result in abnormal structural remodeling of TSH, specifically hypersialylation and increased N-glycan branching. We hypothesize that these altered TSH glycoforms dynamically interact with the TSH receptor. Due to their prolonged circulatory half-life, they may redirect canonical signaling toward sustained, atypical modulation of oncogenic networks, notably the PI3K/Akt/mTOR and MAPK pathways. These proposed signaling alterations could potentially contribute to tumor cell proliferation, epithelial-mesenchymal transition, immune evasion, and potential resistance to multimodal therapies in advanced thyroid carcinomas. These glycomic alterations may represent potential biomarker candidates; however, their diagnostic and prognostic utility remains clinically unvalidated. These findings provide a rationale for investigating whether metabolic regulation and glycosylation-targeted approaches could contribute to future strategies for overcoming treatment resistance in aggressive thyroid carcinomas.