Ketogenic β-hydroxybutyrate-regulated β-hydroxybutyrylation of HSPE1 alleviates neuronal apoptosis in MPTP/MPP+ induced Parkinson's disease models.

Lysine β-hydroxybutyrylation (Kbhb) is an emerging post-translational modification regulated by β-hydroxybutyrate (BHB), a key metabolic intermediate elevated during ketogenic diets. Accumulating evidence indicates that ketogenic diets exert beneficial effects in Parkinson's disease (PD). However, whether BHB-mediated Kbhb modification contributes to these neuroprotective effects remains largely unknown. This study integrates bioinformatics analyses with experimental validation to identify potential Kbhb-related biomarkers associated with PD. Key candidates were further validated using in vivo and in vitro PD models, and downstream regulatory mechanisms were explored through transcriptome sequencing. Through integrative bioinformatics and machine learning analyses, HSPE1 was identified as a central hub gene associated with Kbhb modification in PD. Experimental results demonstrate that Kbhb modification of HSPE1 promotes ubiquitin-mediated degradation, thereby attenuating dopaminergic neuronal apoptosis under PD conditions. Mechanistically, HSPE1 Kbhb modification exerted neuroprotective effects by suppressing the activation of the NF-κB signaling pathway. Our findings reveal HSPE1 as a previously unrecognized target of lysine β-hydroxybutyrylation in PD and uncover a protective role of HSPE1 Kbhb modification in suppressing NF-KB mediated apoptotic signaling.