BDH2, also known as 3-Hydroxybutyrate dehydrogenase type 2, is a short-chain dehydrogenase/reductase family member. It is a rate-limiting catalyzer in the regulation of intracellular iron metabolism and siderophore biogenesis, playing a key role in iron homeostasis, energy metabolism, and apoptosis. It also participates in pathways related to ketone body utilization, with cytosolic ketone bodies potentially entering mitochondria and the tricarboxylic acid cycle. Genetic models, such as KO mouse models, can be valuable for studying its functions [3,8].

In cancer research, BDH2 has been found to act as a tumor suppressor in various cancers. In gastric cancer, its overexpression induced apoptosis and autophagy by promoting Keap1-Nrf2 interaction, increasing Nrf2 ubiquitination, inhibiting the PI3K/Akt/mTOR pathway through ROS accumulation [1]. In lung adenocarcinoma, BDH2 over-expression reduced cell viability, promoted apoptosis, and regulated autophagy via the Akt/mTOR pathway [2]. In hepatocellular carcinoma, BDH2 was down-regulated, and its expression inhibited tumor cell growth, proliferation, and migration, inducing mitochondrial apoptosis and inhibiting autophagy through the unfolded protein response [4]. In leukemia, RAB27B interacted with BDH2 to inhibit leukemic cell proliferation and promote apoptosis [5]. However, in myelodysplastic syndrome, high BDH2 expression was related to a greater risk of leukemia progression, and in de novo cytogenetically normal acute myeloid leukemia, BDH2 was an independent poor prognostic factor with an anti-apoptotic role [7,8]. In embryonic stem cells, Bdh2 deficiency promoted endoderm-biased early differentiation, and in CD4+ T cells of systemic lupus erythematosus, down-regulation of BDH2 modulated iron homeostasis, promoted DNA demethylation, and led to overexpression of immune-related genes [3,6].

In conclusion, BDH2 is crucial for multiple biological processes, especially those related to iron metabolism, energy metabolism, and apoptosis. Model-based research, particularly KO mouse models, has revealed its complex roles in various disease areas, such as cancer, hematological disorders, and autoimmune diseases. Understanding BDH2's functions provides insights into disease mechanisms and may offer potential therapeutic targets.