HM568 Enhances NAD⁺ Biosynthesis to Ameliorate Mitochondrial Dysfunction and Neurotoxicity in Parkinson's Disease...

Parkinson's disease (PD) is closely associated with PARP1 overactivation. Although our previously developed compound HM568 has been shown to alleviate PD pathology, its mechanism of action remained unknown. In this study, we show that HM568 significantly improves behavioral deficits, prevents the loss of dopaminergic neurons, and restores blood-brain barrier integrity and mitochondrial morphology in MPTP/MPP⁺-induced PD models. Proteomic analysis then indicated that the effects of HM568 were enriched in mitochondrial respiratory chain complexes. Building on this clue, we confirmed in cellular models that HM568 counteracts MPP⁺-induced inhibition of complexes I, III, and IV, thereby restoring mitochondrial function. Further mechanistic exploration uncovered that HM568 acts by elevating intracellular NAD⁺ levels, downregulating PARP1 protein expression, and inhibiting its enzymatic activity. Molecular docking indicated a high binding affinity between HM568 and PARP1 (-10.38 kcal/mol). Molecular dynamics simulations provided structural insights into HM568's selective inhibition advantage for PARP1 over PARP2. Our study demonstrates that HM568 corrects mitochondrial dysfunction and energy metabolism imbalance possibly through inhibition of PARP1 and modulation of NAD⁺ metabolism, providing a mechanistic foundation for its potential as a therapeutic agent for Parkinson's disease.