β-Hydroxybutyric Acid Inhibits Mitochondrial Biogenesis via the HDAC2/SIRT7 Signaling Pathway After Intestinal...

β-hydroxybutyric acid (BHB), a key ketone body with energy substrate and epigenetic regulatory roles, has contradictory effects in pathological contexts. Intestinal ischemia-reperfusion (IIR) is a life threatening perioperative complication characterized by metabolic disorders and mitochondrial dysfunction, yet BHB's role in IIR remains unclear. Using C57BL/6 mouse IIR models and Caco2 cell hypoxia-reoxygenation (HR) models, we identified a pathogenic mechanism: IIR induced nearly 10-fold elevation of intestinal BHB, while ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and 3-oxoacid CoA-transferase 1 (OXCT1) were significantly downregulated, blocking BHB's metabolic pathway. Exogenous BHB administration failed to protect the intestine; instead, it selectively inhibited expression of histone deacetylase 2 (HDAC2) (by 30%) and disrupted its nuclear binding to the Sirt7 promoter, promoting Sirt7 gene transcriptional activation (mRNA upregulated by 2-fold). This cascade exacerbated oxidative stress (reactive oxygen species increased by 2.7-fold), reduced adenosine triphosphate levels (by 20%), impaired mitochondrial biogenesis (decreased mitochondrial DNA copy number and mitochondrial transcription factor A (TFAM)/mitochondrial ribosomal proteins (MRPs) expression), and aggravated intestinal barrier dysfunction (Claudin-1 reduced and D-lactate elevated). Notably, HDAC2 overexpression or SIRT7 knockdown reversed these impairments. Our findings uncover a previously unrecognized role of BHB in exacerbating IIR injury via the HDAC2/SIRT7 pathway, providing new insights for protecting pathological intestinal tissues at ischemic risk and targeting mitochondrial biogenesis.