Inhibition of diacylglycerol O-acyltransferase 1 provides neuroprotection by inhibiting ferroptosis in ischemic stroke

作者：Youjie Zeng, Ren Guo, Songhua Chen, Yuxin Lin, Si Cao, Xia Wang, Siyi Zhang, Huilin Xu, Wenxiang Qing, Heng Yang, Wen Ouyang · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01255-w · 被引用次数：11 · 研究领域：Ferroptosis and cancer prognosis、Glycosylation and Glycoproteins Research、Immune cells in cancer

BACKGROUND: Diacylglycerol O-acyltransferase 1 (DGAT1) is crucial for triglyceride synthesis, yet its role in ischemic stroke remains unclear. This study investigated DGAT1 in ischemic stroke using middle cerebral artery occlusion (MCAO) rat models and highly differentiated PC12 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). METHODS: The therapeutic effects of DGAT1 inhibition in MCAO rats were assessed using the Zea-Longa score and 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The effects on highly differentiated PC12 cells subjected to OGD/R were evaluated using the Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Ferroptosis-related mitochondrial damage was evaluated using transmission electron microscope. Additionally, the mechanisms by which DGAT1 inhibition regulates ferroptosis were further explored via immunohistochemistry, immunofluorescence, Western blotting, qPCR, JC-1 assay, and reactive oxygen species (ROS) detection. RESULTS: DGAT1 expression was elevated in both MCAO and OGD/R models. The DGAT1 inhibitor A 922500 improved neurological deficits, reduced infarct volume, and minimized neuronal loss in MCAO rats, while also enhancing cell viability and reducing LDH levels in OGD/R-treated PC12 cells. DGAT1 inhibition significantly alleviated ferroptosis in MCAO rats, as indicated by (i) reduced mitochondrial shortening and cristae disruption, (ii) decreased 4-HNE levels, (iii) reduced MDA and increased SOD, and (iv) lo...