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The role and mechanism of hypoxia in regulating parthanatos in hepatocellular carcinoma

ABSTRACT: Recently, a PARP1-dependent cell-death process termed "parthanatos", driven by DNA damage, has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. The crosstalk between parthanatos and hypoxia remains poorly understood. In our study, we find that despite causing DNA damage, hypoxia fails to induce parthanatos in HCC. Transcriptome sequencing upon MNNG stimulation indicated that the creatine transporter solute carrier family 6, member 8 (SLC6A8) was involved in parthanatos antagonism and malignant phenotypes in hypoxic HCC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289258 | GEO | 2025/07/23

REPOSITORIES: GEO

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The role and mechanism of hypoxia-induced SLC6A8 up-regulation in HCC progression

Project description:Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. We find that the creatine transporter solute carrier family 6, member 8 (SLC6A8) is upregulated in hypoxic HCC cells. Hypoxia-induced creatine accumulation drives metabolic reprogramming and antagonizes parthanatos. Pharmacological inhibition of SLC6A8 represents a promising therapeutic strategy for HCC.

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Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Project description:Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

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Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in Creatine Transporter Deficiency

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Identification of Macrophage Inhibitory Factor as the Parthanatos Dependent AIF Associate Nuclease

Project description:Inhibition or genetic deletion of poly(ADP-ribose) polymerase-1 (PARP-1) is profoundly protective against a number of toxic insults in many organ systems1,2. In the brain the molecular mechanisms underlying PARP-1-dependent cell death (parthanatos) involves mitochondrial apoptosis-inducing factor (AIF) release and translocation to the nucleus resulting in chromatinolysis3-5. However, it is not known how AIF induces chromatinolysis and neuronal death in parthanatos3. Here we show through an unbiased screen of a ~16K human protein microarray followed by a second siRNA-based screen for protection against PARP-1- dependent cell death, that macrophage migration inhibitory factor (MIF)6 is an AIF associated nuclease that is required for cell death following N-methyl-D-aspartate (NMDA) glutamate receptor excitotoxicity and N-methyl-N-nitroso-N- nitroguanidine (MNNG) toxicity in primary neuronal cultures and focal stroke in mice. MIF contains a central four stranded mixed β-sheet flanked by two α- helices on both sides with an αβββαβ topology which is the structural core of many proteins belonging to the PD-D/E(X)K nuclease-like superfamily. MIF possesses previously unknown Mg2+/Ca2+-dependent nuclease activity, cleaving genomic DNA into large 20-50 kb fragments. AIF recruits MIF to the nucleus after NMDA treatment to induce DNA damage and cell death. Disruption of the AIF-MIF interaction prevents MIF recruitment to the nucleus and protects neurons from NMDA excitotoxicity and ischemic injury. Mutation of Glu22 to Gln in the catalytic nuclease domain completely blocks MIF’s nuclease activity, which almost completely inhibits DNA damage and cell death in vitro and in vivo. These findings reveal that MIF is recruited by AIF to the nucleus where it functions as a parthanatos dependent AIF associated nuclease that induces chromatinolysis and neuronal death, providing a new therapeutic target for stroke and other disorders involving parthanatos.

2016-12-19 | GSE65110 | GEO

Single nuclei transcriptomics from lumbar spinal cord of EAE mice treated with MIF nuclease inhibitor PAANIB1

Project description:Central nervous system inflammation is implicated in neurodegeneration across several disorders, including multiple sclerosis (MS). While marked therapeutic progress has been made through the suppression of immune cell trafficking and function, primary neuroprotection in MS remains elusive. This, in part, is due to an incomplete understanding of the molecular signaling pathways involved in immune-mediated neuronal death. Here, we show that parthanatos, a recently described caspase-independent and DNA damage-induced cell death program, contributes to neuron death in the experimental autoimmune encephalomyelitis (EAE) mouse model of autoimmune neuroinflammation. We revealed that DNA damage increases in neurons during EAE, and that neurons are progressively lost over the disease course. Neurons in affected areas display intercellular hallmarks of the parthanatos cascade. Genetic or pharmacologic blockade of the final step in parthanatos, genomic fragmentation by MIF nuclease, reduces neuron loss and disease severity. Transcriptomic characterization of these neurons reveals parthanatos-dependent differences in response to EAE. Together, this work establishes parthanatos as a key mechanism of neuron cell death during neuroinflammation. 

2025-10-24 | GSE304067 | GEO

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