Bdh1, short for β -hydroxybutyrate dehydrogenase 1, is the rate -limiting enzyme in ketone metabolism. It plays a critical role in the conversion between acetoacetate and β -hydroxybutyrate [1,3,4,5]. The presence of β -hydroxybutyrate is essential for initiating lysine β -hydroxybutyrylation (Kbhb) modifications, and histone Kbhb at the H3K9 site is related to transcriptional activation [1]. Bdh1 is involved in various biological processes and diseases, highlighting its biological importance. Genetic models, such as gene knockout mouse models, can be used to study its functions.

In striated muscles, Bdh1 deficiency in mice reveals that this enzyme optimizes fatty acid oxidation (FAO) efficiency and exercise tolerance during acute fasting. Also, muscle Bdh1 flux is crucial for the full adaptive benefits of intermittent time -restricted feeding (iTRF), including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate [2].

In the context of diseases, in diabetic kidney disease (DKD), Bdh1 is downregulated in the kidneys of DKD mouse models, patients with diabetes, and high-glucose-or palmitic acid-induced human renal tubular epithelial cells. Overexpression of Bdh1 in C57 BKS db/db mice can reverse fibrosis, inflammation, and apoptosis in the kidneys [3]. In diabetic cardiomyopathy, genetic deletion of Bdh1 in mice aggravated, while AAV-mediated Bdh1 overexpression attenuated, the diastolic dysfunction and pathogenic progression in hearts from db/db mice [4]. In acute myeloid leukemia (AML), overexpression of Bdh1 in AML cell lines inhibited cell viability and proliferation, while Bdh1 knock-down promoted cell growth, and low Bdh1 expression was associated with worse prognosis in AML patients [7]. Ablation of Bdh1 in T cells of mice aggravated the manifestation of metabolic dysfunction-associated steatohepatitis (MASH) and hindered the therapeutic efficacy of empagliflozin [6].

In summary, Bdh1 is a key enzyme in ketone metabolism with important functions in maintaining normal physiological states of muscles and preventing the progression of various diseases like DKD, diabetic cardiomyopathy, AML, and MASH. The use of gene knockout or conditional knockout mouse models has significantly contributed to understanding the role of Bdh1 in these biological processes and disease conditions, providing potential therapeutic targets for these diseases.