Bdh2, short for 3-Hydroxybutyrate dehydrogenase 2, is a member of the short-chain dehydrogenase/reductase family. It serves as a rate-limiting catalyzer in the regulation of intracellular iron metabolism and siderophore biogenesis, and is involved in processes like iron homeostasis, energy metabolism, and apoptosis. It is also associated with pathways such as Keap1/Nrf2/ARE and PI3K/Akt/mTOR [1-4].

In cancer research, Bdh2 shows tumor-suppressing properties. In gastric cancer, its overexpression induces apoptosis and autophagy by promoting Nrf2 ubiquitination, regulating intracellular ROS levels and the PI3K/Akt/mTOR pathway [1]. Similarly, in lung adenocarcinoma, it promotes apoptosis and autophagy via the Akt/mTOR pathway [2]. In hepatocellular carcinoma, it inhibits tumor cell growth, proliferation, and migration, and induces mitochondrial apoptosis while inhibiting autophagy through the unfolded protein response [3]. In leukemia, RAB27B interacts with Bdh2 to inhibit cell proliferation and promote apoptosis [4]. In myelodysplastic syndrome, high Bdh2 expression is related to a poor prognosis, being involved in cell cycle arrest and inhibition of differentiation in malignant cells [6]. In cytogenetically normal acute myeloid leukemia, Bdh2 has an anti-apoptotic role and is a poor prognostic factor [7]. In systemic lupus erythematosus, down-regulation of Bdh2 in CD4+ T cells modulates iron homeostasis, promoting DNA demethylation [5].

In conclusion, Bdh2 plays crucial roles in multiple biological processes, especially in cancer and autoimmune diseases. Studies, including those potentially using gene knockout (KO) or conditional knockout (CKO) mouse models, have revealed its significance in regulating cell apoptosis, autophagy, and iron-related processes, which could potentially provide new therapeutic targets for related diseases.

References:

1. Liu, Jia-Zhou, Hu, Yi-Lin, Feng, Ying, Mao, Qin-Sheng, Xue, Wan-Jiang. 2020. BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer. In Journal of experimental & clinical cancer research : CR, 39, 123. doi:10.1186/s13046-020-01620-z. https://pubmed.ncbi.nlm.nih.gov/32605589/

2. Nie, Yongli, Mei, Xiong, Cao, Fengjun, Zhu, Xueni. . BDH2 promotes apoptosis and autophagy of lung adenocarcinoma cells via Akt/mTOR pathway. In General physiology and biophysics, 41, 115-122. doi:10.4149/gpb_2022002. https://pubmed.ncbi.nlm.nih.gov/35416174/

3. Liang, Hao, Xiong, Zhiyong, Li, Ruixi, Yao, Zhicheng, Deng, Meihai. 2019. BDH2 is downregulated in hepatocellular carcinoma and acts as a tumor suppressor regulating cell apoptosis and autophagy. In Journal of Cancer, 10, 3735-3745. doi:10.7150/jca.32022. https://pubmed.ncbi.nlm.nih.gov/31333791/

4. Meng, Can, Huang, Li, Fu, Xiangjun, Wu, Bin, Lin, Lie. . RAB27B inhibits proliferation and promotes apoptosis of leukemic cells via 3-Hydroxy butyrate dehydrogenase 2 (BDH2). In Bioengineered, 13, 5103-5112. doi:10.1080/21655979.2022.2036903. https://pubmed.ncbi.nlm.nih.gov/35164665/

5. Zhao, Ming, Li, Meng-Ying, Gao, Xiao-Fei, Wu, Hai-Jing, Lu, Qian-Jin. 2017. Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4+ T cells of systemic lupus erythematosus. In Clinical immunology (Orlando, Fla.), 187, 113-121. doi:10.1016/j.clim.2017.11.002. https://pubmed.ncbi.nlm.nih.gov/29113828/

6. Yang, Wen-Chi, Lin, Sheng-Fung, Wang, Shu-Chen, Wu, Chun-Chieh, Wu, Shih-Chi. 2020. The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome. In International journal of molecular sciences, 21, . doi:10.3390/ijms21093033. https://pubmed.ncbi.nlm.nih.gov/32344823/

7. Yang, Wen-Chi, Tsai, Wan-Chi, Lin, Pai-Mei, Yu, Wen-Hui, Lin, Sheng-Fung. 2013. Human BDH2, an anti-apoptosis factor, is a novel poor prognostic factor for de novo cytogenetically normal acute myeloid leukemia. In Journal of biomedical science, 20, 58. doi:10.1186/1423-0127-20-58. https://pubmed.ncbi.nlm.nih.gov/23941109/