Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(22)

Published: Nov. 14, 2024

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show lactate production patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic histone lactylation, activating modification leads immunosuppressive transcriptional programs suppression of phagocytosis via upregulation CD47, "don't eat me" signal, in cells. Leveraging these findings, pharmacologic targeting augments efficacy anti-CD47 therapy. Mechanistically, lactylated interacts the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, binds acetyltransferase (HAT) EP300 induce increased substrate specificity lactyl-CoA shift cytokine profile. Targeting inhibits growth both cell–intrinsic phagocytosis. Collectively, results suggest mediates metabolism-induced contributes CD47-dependent immune evasion, which can be leveraged augment immuno-oncology therapies.

Language: Английский

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Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8922 - 8922

Published: Aug. 16, 2024

Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes both physiological pathological conditions, highlighting their adaptive plasticity diverse functions. Under normal modulate synaptic activity, recycle neurotransmitters, maintain blood–brain barrier, ensuring balanced supply protection against oxidative stress. However, response to central nervous system pathologies such as neurotrauma, stroke, infections, neurodegenerative diseases like Alzheimer’s Huntington’s disease, undergo significant morphological, molecular, changes. Reactive upregulate fatty acid oxidation meet increased demands, which can be protective acute settings but may exacerbate chronic inflammation disease progression. emphasizes need for advanced genetic, tools further understand astrocyte heterogeneity reprogramming states.

Language: Английский

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Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury

Neuroscience, Journal Year: 2025, Volume and Issue: 567, P. 227 - 234

Published: Jan. 7, 2025

Language: Английский

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Neuroglial Dysregulation in Autism Spectrum Disorder: Pathogenetic Insights, Genetic Threads, and Therapeutic Horizons

Neuroglia, Journal Year: 2025, Volume and Issue: 6(1), P. 11 - 11

Published: March 1, 2025

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by challenges in social communication, restricted interests, and repetitive behaviors. Recent studies highlight the crucial roles of neuroglial cells—astrocytes, microglia, oligodendrocytes—in synaptic function, neural connectivity, neuroinflammation. These findings offer fresh perspective on ASD pathophysiology. This review synthesizes current knowledge dysfunction ASD, emphasizing its role pathophysiological mechanisms, genetic influences, potential therapeutic strategies. Methods: We conducted comprehensive literature review, integrating insights from neuroscience, molecular biology, clinical studies. Special focus was given to glial-mediated neuroinflammatory plasticity regulation, impact mutations signaling homeostasis. Results: Neuroglial evident abnormal pruning impaired astrocytic glutamate defective oligodendrocyte-driven myelination, which collectively disrupt neuronal architecture. Emerging therapies targeting these pathways, including anti-inflammatory drugs, microglial modulators, cell-based approaches, show promise alleviating key symptoms. Additionally, advanced interventions such as gene editing glial progenitor therapy present opportunities correct underlying dysfunction. Conclusions: establishes framework for understanding contributions ASD. By diverse disciplines, it enhances our pathophysiology paves way novel strategies pathways.

Language: Английский

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Astrocyte Dysfunctions in Obsessive Compulsive Disorder: Rethinking Neurobiology and Therapeutic Targets

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(5)

Published: May 1, 2025

ABSTRACT Obsessive‐compulsive disorder (OCD) has long been conceptualized as a neuron‐centric of cortico‐striato‐thalamo‐cortical (CSTC) circuit dysregulation. However, growing body evidence is now reframing this narrative, placing astrocytes—once relegated to passive support roles—at the center OCD pathophysiology. Astrocytes are critical regulators glutamate and GABA homeostasis, calcium signaling, synaptic plasticity, all which disrupted in OCD. Recent high‐resolution molecular proteomic studies reveal that specific astrocyte subpopulations, including Crym ‐positive astrocytes, directly shape excitatory/inhibitory balance control perseverative behaviors by modulating presynaptic inputs from orbitofrontal cortex. Disruptions astrocytic neurotransmitter clearance dopamine metabolism amplify CSTC hyperactivity reinforce compulsions. This review reframes neuro‐glial dysfunctions, proposing targeting metabolism, structural plasticity may unlock transformative therapeutic strategies. By integrating human animal data, we advocate for glial‐centric model not only enhances mechanistic understanding but also opens new frontiers precision treatment. image

Language: Английский

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Correlation of biochemical markers and inflammatory cytokines in autism spectrum disorder (ASD)

BMC Pediatrics, Journal Year: 2024, Volume and Issue: 24(1)

Published: Nov. 1, 2024

Autism Spectrum Disorder (ASD) is a disorder that severely affects neurodevelopment, and its underlying causes are not yet entirely understood. Research suggests there may be connection between the occurrence of ASD changes in immune responses. This study aims to know if some biochemical inflammatory cytokines promising biomarkers for whether they involved pathogenesis ASD.

Language: Английский

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Developmental Neurotoxicity of Bisphenol F and Bisphenol S in Animal Model Systems: A Literature Review

NeuroToxicology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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The Metabolic Journey of Microglia from Early Development to Adulthood

Glial health research., Journal Year: 2024, Volume and Issue: unknown, P. 100003 - 100003

Published: Dec. 1, 2024

Language: Английский

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