TET2: a critical regulatory hub with broad therapeutic implications across human diseases

Abstract

Ten-Eleven Translocation 2 (TET2) is a pivotal α-ketoglutarate and Fe2+-dependent dioxygenase belonging to the TET family, governing epigenetic homeostasis through DNA, RNA, and histone modifications. Its central function involves the iterative oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further derivatives, initiating active DNA demethylation. Beyond this, TET2 catalyzes RNA m5C oxidation and interacts with histone modifiers, thus modulating diverse cellular processes. Physiologically, TET2 is indispensable for hematopoietic stem cell (HSC) function, genomic stability, and the resolution of inflammation. Its dysregulation, often driven by somatic mutations, is implicated across a broad spectrum of human diseases. These include hematological malignancies, solid tumors, inflammatory disorders, cardiovascular diseases (CVD), metabolic abnormalities, and neurological conditions. Notably, TET2 exhibits strong context dependency, functioning as a tumor suppressor in myeloid malignancies while exerting distinct immunomodulatory roles in certain solid tumors. This review systematically summarizes recent advances in the molecular mechanisms and physiological functions of TET2, and highlights its disease-specific roles and promising therapeutic strategies. We also discuss unresolved challenges and future research directions to facilitate the clinical translation of TET2-related epigenetic findings.