27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging, suppressed by Deferoxamine

作者：Chunyang Yu, Wencheng Wang, Lei Shi, Rui Ma, Yawen Zhang, Chun Zhang, Xuewei Wang, Tianqi Wang, Yan Zheng, Jianying Tian · 发表于：npj Aging · 年份：2025 · DOI：10.1038/s41514-025-00303-3 · 被引用次数：4 · 研究领域：Cholesterol and Lipid Metabolism、Neuroinflammation and Neurodegeneration Mechanisms、Ferroptosis and cancer prognosis

Brain aging is a major factor in cognitive decline and Alzheimer's disease (AD) progression. Aging-induced microglial senescence critically drives inflammaging and brain aging processes. Nevertheless, the underlying reasons and mechanisms that promote microglial aging remain unclear. This study explores how 27-hydroxycholesterol (27-OHC), a key oxysterol, accelerates brain aging by promoting microglial senescence, iron overload, and neuroinflammation. Clinically, we observed a significant inverse correlation between plasma 27-OHC levels and Mini-Mental State Examination (MMSE) scores in AD patients, accompanied by reduced 24S-OHC concentrations. Experimental studies revealed that 27-OHC administration in mice induced hippocampal-dependent cognitive impairment and anxiety-like behaviors, concurrent with elevated expression of cellular senescence markers (P21, P16, SA-β-Gal) and M1 microglial polarization. In BV-2 cells, 27-OHC disrupted iron homeostasis (DMT1/ferritin/GPX4 dysregulation), elevating ROS and impairing mitochondrial function. Deferoxamine (DFX) mitigated microglial senescence and ferroptosis. These findings establish the 27-OHC-iron axis as a novel therapeutic target for combating cholesterol-driven neurodegeneration.