H4K12 Lactylation Impairs Dopaminergic Neuron Energy Metabolism via the HIF‐1α/NDUFS1 Pathway in Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra, with mitochondrial dysfunction central to its pathology. Recent studies have linked lactate-accumulating in PD due to mitochondrial dysfunction-to disease mechanisms through lactylation, a novel post-translational modification. However, the specific pathogenic role of lactylation in PD remains unclear. Here, H4K12 was identified as a key histone lactylation site and its role in PD pathogenesis was investigated. Plasma lactate and global histone lactylation were elevated in 83 PD patients compared with 83 Health controls. Consistently, lactate and H4K12la were upregulated in both PD mouse and cell models. Genome-wide CUT&Tag and RNA sequencing revealed that H4K12la enrichment at the HIF-1α promoter upregulates HIF-1α, which in turn represses NDUFS1 via direct promoter binding, impairing mitochondrial respiration and disrupted cellular energy supply. Upstream, P300 was identified as a critical catalyst of H4K12la; P300 directly bound to and sustained H4K12la levels. Collectively, these findings delineate a pathogenic signaling axis-the P300/H4K12la/HIF-1α/NDUFS1 axis-that disrupts energy homeostasis in DA neurons. Importantly, the pharmacological inhibition of this axis with 2-deoxy-D-glucose or PX-478 rescued motor deficits in PD model mice, thereby highlighting its therapeutic potential for PD.