The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer.

One of the fastest-growing malignant tumors in the world is thyroid cancer (TC), and there are currently no effective treatments for its aggressive subtypes, such as anaplastic carcinoma and radioactive iodine-refractory differentiated thyroid carcinoma. Recent investigations have shown that DNA methylation and metabolic reprogramming are not independent events, but rather create a closely interconnected, mutually reinforcing network of carcinogenic processes. On the one hand, metabolic reprogramming influences the methylation status of tumor suppressor genes and thyroid function genes by dynamically regulating the activity of DNA methyltransferases and demethylases through important metabolites (such as S-adenosylmethionine, or SAM, and α-KG) and oncogenic signaling pathways (like PI3K/AKT). Conversely, DNA methylation systematically remodels cellular glucose, lipid, and amino acid metabolism by directly silencing metabolic enzyme genes (such as FASN and GLS) and thyroid differentiation markers (such as NIS) to fulfill its proliferative demands. Tumor growth, treatment resistance, and the development of an immunosuppressive microenvironment are all fueled by this ongoing bidirectional interaction, which creates a self-reinforcing oncogenic cycle. As a result, the limitations of earlier discrete debates on DNA methylation or metabolic reprogramming are overcome in this review. To methodically clarify their crosstalk mechanisms, a theoretical framework based on the "DNA methylation-metabolism axis" is suggested. Additionally, it suggests multimodal therapy approaches that focus on this axis. Incorporating biomimetic delivery technologies, combined with epigenetic, metabolic, and immunotherapies, to lay the groundwork for comprehending TC causes and creating targeted treatments.