In HLRCC, FH loss leads to an accumulation of fumarate, a competitive inhibitor of α-KG-dependent prolyl hydroxylase (PHD) that hydroxylates HIFs for degradation, thus activating oncogenic hypoxia pathways (Isaacs et al., 2005; Pollard et al., 2007). Here, FH is linked to hereditary leiomyomatosis and renal cell cancer.