BDH2 (3-hydroxybutyrate dehydrogenase 2) is a NAD(H)-dependent oxidoreductase with dual roles in iron metabolism and cancer suppression. Biochemically, BDH2 catalyzes stereoselective conversion of 4-oxo-L-proline to cis-4-hydroxy-L-proline and synthesizes 2,5-dihydroxybenzoate (2,5-DHBA), a siderophore that chelates cytoplasmic iron and facilitates its mitochondrial import for heme synthesis and bioenergetics 1. BDH2 localizes at mitochondria-lysosome contacts to mediate inter-organelle iron redistribution, supporting mitochondrial function and lysosomal pH regulation 2. In cancer biology, BDH2 functions as a tumor suppressor across multiple malignancies. BDH2 overexpression triggers ROS-induced apoptosis and autophagy in gastric cancer by promoting Nrf2 ubiquitination and degradation, thereby inhibiting the PI3K/Akt/mTOR pathway 3. Similar mechanisms apply in lung adenocarcinoma 4 and leukemia 5. In colorectal cancer, BDH2 increases 5-FU chemosensitivity by promoting GLIPR1 promoter methylation 6. Low BDH2 expression correlates with poor survival and higher leukemia transformation risk in myelodysplastic syndrome patients 7. Beyond cancer, iron-dependent BDH2 activity regulates pathogenic T cell differentiation in lupus through the miR-21/BDH2/TET axis 8, while inflammation and ER stress downregulate BDH2 in macrophages, dysregulating iron homeostasis 9.