ABSTRACT 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.
Shi et al. (Thu,) studied this question.