Fumarate and succinate, which accumulate in tumors due to mutations in the tumor suppressor genes FH and SDH, inhibit α-KG-dependent dioxygenases, including histone and DNA demethylases. These metabolites act as competitive inhibitors of α-KG, leading to broad inhibition of α-KG-dependent enzymes. This inhibition results in altered histone and DNA methylation patterns, contributing to tumorigenesis. The study demonstrates that FH and SDH mutations lead to the accumulation of fumarate and succinate, which in turn inhibit the activity of α-KG-dependent dioxygenases, including KDMs, PHDs, and TETs. This inhibition disrupts normal epigenetic regulation, leading to changes in histone and DNA methylation. The findings suggest that the accumulation of fumarate and succinate in FH and SDH mutant tumors contributes to the development of cancer by altering epigenetic modifications. The study also shows that tumor-derived FH and SDH mutants inhibit α-KG-dependent dioxygenases, leading to changes in histone methylation and HIF1α levels. These results highlight the role of FH and SDH mutations in tumor progression through the accumulation of fumarate and succinate, which inhibit key enzymes involved in epigenetic regulation. The study provides insights into the mechanisms by which FH and SDH mutations contribute to tumorigenesis through the disruption of α-KG-dependent dioxygenase activity and subsequent epigenetic changes.Fumarate and succinate, which accumulate in tumors due to mutations in the tumor suppressor genes FH and SDH, inhibit α-KG-dependent dioxygenases, including histone and DNA demethylases. These metabolites act as competitive inhibitors of α-KG, leading to broad inhibition of α-KG-dependent enzymes. This inhibition results in altered histone and DNA methylation patterns, contributing to tumorigenesis. The study demonstrates that FH and SDH mutations lead to the accumulation of fumarate and succinate, which in turn inhibit the activity of α-KG-dependent dioxygenases, including KDMs, PHDs, and TETs. This inhibition disrupts normal epigenetic regulation, leading to changes in histone and DNA methylation. The findings suggest that the accumulation of fumarate and succinate in FH and SDH mutant tumors contributes to the development of cancer by altering epigenetic modifications. The study also shows that tumor-derived FH and SDH mutants inhibit α-KG-dependent dioxygenases, leading to changes in histone methylation and HIF1α levels. These results highlight the role of FH and SDH mutations in tumor progression through the accumulation of fumarate and succinate, which inhibit key enzymes involved in epigenetic regulation. The study provides insights into the mechanisms by which FH and SDH mutations contribute to tumorigenesis through the disruption of α-KG-dependent dioxygenase activity and subsequent epigenetic changes.