2-Hydroxyglutarate in onco-pathway: a metabolic driver of proto-oncogene activation

Metabolic alteration has emerged as a hallmark of cancer, reshaping cellular energetics and biosynthetic pathways through enzyme denaturation, mutations, acidic pH, and hypoxia to sustain uncontrolled proliferation. Under these conditions, enzymes exhibit aberrant activity, disrupting wild-type processes and generating small chiral or achiral metabolites that often function as oncogene activators. Among these oncometabolites, 2HG has gained prominence due to its chiral forms, D-2HG and L-2HG, which structurally mimic α-KG and competitively inhibit α-KG-dependent dioxygenases. This enantioselective interference perturbs epigenetic regulation, redox balance, DNA repair, and cell signaling, thereby orchestrating tumor initiation and progression. This review provides an integrated overview of the factors driving chiral discrimination of 2HG, its contribution to tumor heterogeneity, and its influence on therapy resistance. By unravelling the molecular intricacies of 2HG enantiomers, this work highlights their significance as biomarkers and therapeutic targets, offering new avenues to disrupt cancer signaling and improve patient outcomes.