oncometaboliteinduced

Oncometabolite-induced describes cellular and physiological changes driven by the accumulation of oncometabolites—metabolites whose increased levels promote tumor growth and malignant transformation. This concept arises from observations that certain metabolites, when dysregulated, can alter signaling, epigenetic regulation, and metabolism in ways that favor cancer development. Oncometabolites most often arise from mutations in metabolic enzymes, such as isocitrate dehydrogenase (IDH1/IDH2) producing 2-hydroxyglutarate, succinate dehydrogenase (SDH) mutations leading to succinate accumulation, or fumarate hydratase (FH) mutations causing fumarate buildup.

These metabolites broadly inhibit alpha-ketoglutarate-dependent dioxygenases, including TET family DNA demethylases and JmjC-domain histone demethylases, causing widespread changes in DNA and histone methylation and contributing to aberrant gene expression and blocked cellular differentiation. They can also affect hypoxia signaling by inhibiting prolyl hydroxylases, stabilizing HIF transcription factors independent of oxygen levels.

Biological consequences include epigenetic reprogramming, altered cell fate, metabolic remodeling, and, in many contexts, enhanced proliferative capacity and survival under stress. Oncometabolite-induced changes have been linked to tumorigenesis in several cancers, notably IDH-mutant gliomas and chondrosarcomas, as well as paragangliomas.

From a clinical perspective, detection of oncometabolites and drugs that target their production or downstream effects are active areas of research, with IDH inhibitors representing a model for metabolic targeted therapy and epigenetic therapies showing potential in certain contexts.