ArticleCell death & disease2024
Sphk1/S1P pathway promotes blood-brain barrier breakdown after intracerebral hemorrhage through inducing Nlrp3-mediated endothelial cell pyroptosis.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Loss of Pericytic Integrin-β1 Exacerbates Blood-Brain Barrier Damage and Hemorrhagic Brain Injury.Stroke · 2026Article
- Irisin Restrains Oligodendroglial Ferroptosis to Preserve White Matter After Traumatic Brain Injury via AMPK Activation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Potential Role of Sphingosine-1-Phosphate and Its Receptors in the Reparative Processes of the Adult Brain.International journal of molecular sciences · 2026Review
- Endothelial Cell TRIM47 Triggers Blood-Brain Barrier Disruption via CYLD Ubiquitination Degradation in an Intracerebral Hemorrhage Model.Neuroscience bulletin · 2026Article
- Molecular Regulation of Pyroptosis in Alzheimer's Disease: Linking Neuroinflammation, Cell Death, and Therapeutic Targeting.Molecular neurobiology · 2026Review
- Exerkine-Mediated Regulation of the NLRP3 Inflammasome in Neuroprotection: Mechanistic Insights and the Role of Exercise.Molecular neurobiology · 2026Review
- The Sphingolipid Balance and Endothelial Dysfunction in Lysosomal Storage Diseases: Shared Mechanisms in Gaucher, Niemann-Pick and Fabry Disease.International journal of molecular sciences · 2026Review
- Midazolam Exerts Sedative Effects by Differentially Modulating Cortical Pyramidal Neurons and PV Interneurons.CNS neuroscience & therapeutics · 2026Article
- Circulating sphingosine-1-phosphate depletion is associated with endothelial activation and altered brain-endothelial S1P pathway expression in ischemic stroke.Fluids and barriers of the CNS · 2026Article
- Profiling of macroelements and microelements in colorectal cancer patients and their clinicopathological characteristics.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Article
- PKM2 preconditioning protects endothelial cells from pyroptosis and BBB disruption via NRF2/TRX/TXNIP signaling in neonatal hypoxic-ischemic brain injury.Journal of neuroinflammation · 2026Article
- Neuroinflammatory mechanisms and pharmacological advances in autism spectrum disorder: from inflammatory pathways to targeted interventions.Frontiers in immunology · 2026Review
- Sphingolipid-Neuroinflammation Axis in Parkinson's Disease: Focus on S1P/SPHK1-NF‑κB Signaling.Journal of inflammation research · 2026Review
- NF-κB signaling as a critical inflammatory node in pulmonary arterial hypertension: from vascular remodeling to right heart failure.Frontiers in immunology · 2026Review
- Disulfiram Prevents Blood-Brain Barrier Disruption in Epileptic Mice by Inhibiting Astrocyte Pyroptosis to Improve Seizure Activity.Molecular neurobiology · 2025Article
- Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications.Fluids and barriers of the CNS · 2025Review
- Chaihu Guizhi Ganjiang Decoction ameliorates chronic pancreatitis by modulating the SK1/S1P signaling pathway.Journal of natural medicines · 2025Article
- Reactive astrocyte-derived exosomes enhance intracranial lymphatic drainage in mice after intracranial hemorrhage.Fluids and barriers of the CNS · 2025Article
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Authors and funding
12 authors.
Funding
Abstract
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and limited therapeutic options. The blood-brain barrier (BBB) breakdown post-ICH exacerbates secondary brain injury, highlighting the need for targeted therapies to preserve the BBB integrity. We aim to investigate the role of the Sphk1/S1P pathway in BBB breakdown following ICH and to evaluate the therapeutic potential of Sphk1 inhibition in mitigating this breakdown. Using a combination of human patient samples, mouse models of ICH, and in vitro cellular assays, we assessed the expression levels of Sphk1/S1P after ICH and changes of the BBB after ICH. The Sphk1 inhibitor PF543 and siRNAs were utilized to explore the pathway's impact on BBB integrity and the underlying mechanisms. The results indicate significant upregulation of Sphk1/S1P in the peri-hematomal brain tissue after ICH, which correlates with increased BBB leakage. Pharmacological inhibition of Sphk1 with PF543 attenuates BBB leakage, reduces hematoma volume, and improves neurological outcomes in mice. At the molecular and ultrastructural level, Sphk1 inhibition protects the BBB integrity by preserving tight junction proteins and suppressing endothelial transcytosis. Furthermore, mechanistic studies reveal that Sphk1 promotes Nlrp3-mediated pyroptosis of brain endothelial cells through the ERK1/2 signaling pathway. Taken together, the Sphk1/S1P pathway plays a critical role in ICH-induced BBB breakdown, and its inhibition represents a promising therapeutic strategy for ICH management.
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