FKBP4-mediated reprogramming of H3K4bhb at energy metabolism ameliorates ischemic acute kidney injury.

Renal ischemia-reperfusion injury (IRI), a cause of acute kidney injury (AKI), involves mitochondrial dysfunction. Under metabolic stress, the ketone body β-hydroxybutyrate functions as an alternative substrate for mitochondrial energy production, the underlying mechanisms remain incompletely understood. Here, we identify FK506 binding protein 4 (FKBP4) as a critical regulator of mitochondrial energy metabolism in AKI. A bilateral renal IRI mouse model was established with pretreatment of ketogenic diet (KD) or sodium β-hydroxybutyrate (BHBNa). Metabolomics and bulk RNA-seq were performed to assess mitochondrial oxidative stress and energy metabolism. In vitro, human renal tubular epithelial cells (HK-2) underwent hypoxia/reoxygenation (H/R) to mimic ischemia/hypoxia injury, with mitochondrial energy metabolism evaluated via the seahorse assay. Chromatin immunoprecipitation (ChIP) was used to identify downstream targets of β-hydroxybutyrylation of histone H3K4 (H3K4bhb). Administration of KD or BHBNa ameliorated renal dysfunction at 24 h post-ischemia. The renoprotective effect of BHBNa was mediated by FKBP4. In HK-2 cells, both overexpression and knockdown of FKBP4 significantly altered mitochondrial energy metabolism. Mechanistically, β-hydroxybutyrate-induced autophagy was dependent on FKBP4, and its knockdown suppressed both autophagy and mitochondrial oxidative phosphorylation (OXPHOS). FKBP4 functions as a co-chaperone that binds β-hydroxybutyryllysine (Kbhb) and facilitates nuclear receptor trafficking to mediate conjugation of H3K4bhb. This ketone body-induced epigenetic modification enhances mitochondrial OXPHOS in renal tubules, providing critical energy support during renal IRI. Our findings indicate that supplemental ketone bodies mitigate IRI-induced AKI, and identify FKBP4 as a central coordinator of mitochondrial energy metabolism through upregulation of autophagy and mediation of H3K4bhb.