ArticleMolecular medicine (Cambridge, Mass.)2025
Inhibition of diacylglycerol O-acyltransferase 1 provides neuroprotection by inhibiting ferroptosis in ischemic stroke.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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7 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Histological Insights into the Neuroprotective Effects of Antioxidant Peptides and Small Molecules in Cerebral Ischemia.Molecules (Basel, Switzerland) · 2025Pooled it
- Design, synthesis and biological evaluation of donepezil-safinamide hybrids as dual AChE and MAO-B inhibitor for Alzheimer's disease treatment.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- HIV-1 Tat-induced VAPB disruption initiates a cascade of organellar failures culminating in neuronal lipid accumulation.Journal of lipid research · 2026Article
- Sugiol Alleviates Cerebral Ischemia/Reperfusion Injury in the Early Phase Involving the LRRK2/NF-κB Pathway.Cell biochemistry and biophysics · 2026Article
- Hypoxia-inducible factor 1-alpha: a dual regulator of ferroptosis in ischemic stroke and a promising therapeutic target.Frontiers in neurology · 2026Review
- Iron metabolism dysregulation and post-stroke cognitive impairment: mechanisms and therapeutic perspectives.Frontiers in neurology · 2026Review
- Germline Disruption of Retinal Pigment Epithelium-Expressed Zebrafish rlbp1bFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
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11 authors.
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Abstract
backgroundDiacylglycerol 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).
methodsThe 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.
resultsDGAT1 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) lowered levels of inflammatory factors (IL-6, MCP-1, and TNF-α). Moreover, both in vivo and in vitro experiments showed that DGAT1 inhibition significantly increased Gpx4 levels, whereas lentiviral delivery of Gpx4 shRNA markedly reversed its beneficial effects. In MCAO rats, Gpx4 shRNA significantly elevated 4-HNE levels and exacerbated ferroptosis-related mitochondrial damage. In vitro, DGAT1 inhibition increased mitochondrial membrane potential and reduced ROS, whereas rotenone, a mitochondrial function inhibitor, decreased Gpx4 and impaired cell viability. Furthermore, DGAT1 inhibition significantly upregulated the key β-oxidation gene Cpt1a, whereas etomoxir, a β-oxidation inhibitor, reduced cell viability and mitochondrial membrane potential, increased ROS, and downregulated Gpx4.
conclusionsOur study suggests that DGAT1 inhibition may enhance β-oxidation and mitochondrial function, thereby increasing Gpx4 levels, suppressing ferroptosis, and ultimately exerting neuroprotective effects in ischemic stroke.
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