Targeting HDAC3 Suppresses Ferroptosis and Demyelination in White Matter Injury by Restoring PDK4‐Mediated Iron Homeostasis

作者：Ting Xu, Lisha Ye, Wenfeng Li, Fangming Liu, Tianjiao Wei, Wenhui Gu, Lihua Xu, Mengdie Fang, Qianqian Luo, Chuanjie Wu, Guohua Wang · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1111/cns.70471 · 被引用次数：4 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Genetics and Neurodevelopmental Disorders

AIM: White matter injury (WMI), characterized by white matter degeneration and iron deposition, contributes to neurological dysfunction. Histone deacetylase 3 (HDAC3) is implicated in neurodegenerative processes, yet its role in WMI-associated ferroptosis remains unclear. METHODS: Clinical assessments in WMI patients revealed correlations between serum iron, α-synuclein, and antioxidant levels and MRI-confirmed white matter degeneration. In a cuprizone-induced demyelination mouse model, white matter integrity, oligodendrocyte dysfunction, iron accumulation, and lipid peroxidation were evaluated through behavioral testing, histological staining, and biochemical analyses. To identify potential molecular targets of HDAC3-mediated ferroptosis, CUT&Tag sequencing was performed. The involvement of this pathway was further validated in vitro using iron overload assays and in vivo through HDAC3 overexpression via AAV vectors. RESULTS: In the present study, HDAC3 expression was elevated following demyelination and was suppressed by RGFP966 treatment. Brain MRI findings from clinical patients and histological analyses in CPZ-treated mice revealed disrupted iron metabolism following white matter injury, likely driven by increased iron deposition and lipid peroxidation in the affected regions. HDAC3 inhibition alleviated oligodendrocyte lineage dysfunction, preserved myelin integrity, and mitigated cognitive and motor deficits induced by demyelination. CUT&Tag sequencing suggested that t...