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MPTP and rotenone cause dopaminergic neuronal death by increasing DDIT4 promoter lactylation

   
@article{APS11535,
	author = {Jing-chao Hong and Yu-shu Yang and Si-han He and Juan-juan Huang and Xin-rui Zhang and Fang-fang Zeng and Jie-qiong Tan and Hai-long Han and Zhuo-hua Zhang},
	title = {MPTP and rotenone cause dopaminergic neuronal death by increasing DDIT4 promoter lactylation},
	journal = {Acta Pharmacologica Sinica},
	volume = {47},
	number = {6},
	year = {2026},
	keywords = {},
	abstract = {Environmental toxicants such as MPTP and rotenone induce Parkinsonism in both humans and animals. Lactate-driven histone lactylation has recently been implicated in microglial activation and broader CNS pathology. However, its role in dopaminergic (DA) neurons and Parkinson’s disease (PD)-related toxicant responses remains unclear. In this study, we investigated whether neurotoxicant-induced histone lactylation contributes to PD pathogenesis. SH-SY5Y cells were exposed to MPP+ (5 mM) or rotenone (5 μM) for 24 h. A mouse model of PD was established by injection of MPTP (25 mg/kg) for 5 days. We showed that PD-related neurotoxicants increased intracellular lactate levels, promoting histone lactylation in SH-SY5Y cells by suppressing PDH complex activity. By integrating RNA-seq and ChIP-seq analyses, we identified the DDIT4 gene as a lactylation target in response to MPP+ and rotenone. A pharmacological reduction in lactate production or inhibition of lactylation with sodium dichloroacetate (DCA) suppressed DDIT4 promoter lactylation and expression, reduced MPP+- and rotenone-induced cell death in SH-SY5Y cells in vitro and partially protected against MPTP-induced TH-positive DA neuron loss in the brains of MPTP-treated mice in vivo. We demonstrated that DDIT4 was upregulated in the AGTR1/SOX6-positive dopaminergic subpopulation that was highly susceptible to loss in PD patients. These results provide the first evidence that environmental toxicity-induced metabolic alterations drive histone lactylation of the DDIT4 promoter, directly linking a known PD stress effector gene to a lactate-epigenetic signal underlying DA neuron loss. This study reveals a lactate-epigenetic axis that contributes to environmental toxicant-induced Parkinsonism and identifies lactate metabolism and histone lactylation as promising targets for further preclinical investigation.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11535}
}