Bdh1, short for β-Hydroxybutyrate dehydrogenase 1, is the rate-limiting enzyme in ketone metabolism. It plays a crucial role in the conversion between acetoacetate and β-hydroxybutyrate. The presence of β-hydroxybutyrate is essential for initiating lysine β-hydroxybutyrylation (Kbhb) modifications. Bdh1 is involved in multiple biological processes, with its function being studied using various genetic models [1,3,4,5].

In lung adenocarcinoma, Bdh1 is overexpressed and modulates intracellular Kbhb modification levels. It regulates LRRC31, a downstream target gene, and inhibitors like pimozide and crizotinib show a synergistic inhibitory effect on LUAD cell proliferation [1]. In skeletal and cardiac muscles, Bdh1 optimizes fatty acid oxidation efficiency and exercise tolerance during acute fasting. Mice with Bdh1 deficiency in striated muscles helped discover its role in conferring the full adaptive benefits of intermittent time-restricted feeding [2]. In diabetic kidney disease, Bdh1 is downregulated, and its overexpression or βOHB treatment protects renal tubular epithelial cells. Adeno-associated virus 9-mediated Bdh1 renal expression reverses fibrosis, inflammation, and apoptosis in diabetic mice [3]. Similar findings are seen in diabetic cardiomyopathy, where Bdh1 is diminished, and its overexpression alleviates the disease through inhibiting H3K9bhb-mediated transcriptional activation of LCN2 [4]. In a MAFLD mouse model, Bdh1 overexpression ameliorates hepatic injury by activating Nrf2, while its knockdown in LO2 cells leads to ROS overproduction [5]. In MASH, SGLT2 inhibitor promotes ketogenesis by elevating Bdh1 expression in CD8+ T cells, reducing liver injury, and ablation of Bdh1 in T cells aggravates MASH [6]. In acute myeloid leukemia, Bdh1 expression is lower in AML blasts compared to normal HSCs, and overexpression of Bdh1 inhibits AML cell viability and proliferation [7]. In liver cancer, Bdh1 mRNA expression is decreased, and it is an independent predictor of patient prognosis [8].

In conclusion, Bdh1 is a key enzyme in ketone metabolism with a significant impact on various biological processes and diseases. Studies using gene knockout or conditional knockout mouse models have revealed its role in lung adenocarcinoma, muscle metabolic remodeling, diabetic kidney and heart diseases, MAFLD, MASH, acute myeloid leukemia, and liver cancer. Understanding Bdh1's function provides potential therapeutic targets for these diseases.

References:

1. Huang, Jingjing, Liang, Lu, Jiang, Shiyao, Cong, Li, Jiang, Yiqun. 2023. BDH1-mediated LRRC31 regulation dependent on histone lysine β-hydroxybutyrylation to promote lung adenocarcinoma progression. In MedComm, 4, e449. doi:10.1002/mco2.449. https://pubmed.ncbi.nlm.nih.gov/38098610/

2. Williams, Ashley S, Crown, Scott B, Lyons, Scott P, Zhang, Guo-Fang, Muoio, Deborah M. . Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding. In Cell metabolism, 36, 422-437.e8. doi:10.1016/j.cmet.2024.01.007. https://pubmed.ncbi.nlm.nih.gov/38325337/

3. Wan, Sheng-Rong, Teng, Fang-Yuan, Fan, Wei, Jiang, Zong-Zhe, Xu, Yong. 2023. BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway. In Aging, 15, 13384-13410. doi:10.18632/aging.205248. https://pubmed.ncbi.nlm.nih.gov/38015723/

4. Xu, Bu-Tuo, Wan, Sheng-Rong, Wu, Qi, Xu, Yong, Jiang, Zong-Zhe. 2025. BDH1 overexpression alleviates diabetic cardiomyopathy through inhibiting H3K9bhb-mediated transcriptional activation of LCN2. In Cardiovascular diabetology, 24, 101. doi:10.1186/s12933-025-02646-3. https://pubmed.ncbi.nlm.nih.gov/40022118/

5. Xu, Bu-Tuo, Teng, Fang-Yuan, Wu, Qi, Xu, Yong, Jiang, Zong-Zhe. 2022. Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model. In Cell death discovery, 8, 49. doi:10.1038/s41420-022-00840-w. https://pubmed.ncbi.nlm.nih.gov/35115498/

6. Liu, Wenhui, You, Danming, Lin, Jiayang, Yang, Wei, Zhang, Huijie. 2024. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation. In Cell metabolism, 36, 2245-2261.e6. doi:10.1016/j.cmet.2024.08.005. https://pubmed.ncbi.nlm.nih.gov/39243758/

7. Han, Fei, Zhao, Huanhuan, Lu, Jun, Wang, Qishan, Jiang, Xi. 2021. Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia. In Frontiers in oncology, 11, 694594. doi:10.3389/fonc.2021.694594. https://pubmed.ncbi.nlm.nih.gov/34150668/

8. Liu, Zhicheng, Li, Yanqing, Liu, Ying, Jiao, Yan, Liu, Yunpeng. . Expression and clinical significance of BDH1 in liver cancer. In Medicine, 100, e28013. doi:10.1097/MD.0000000000028013. https://pubmed.ncbi.nlm.nih.gov/35049211/