Erythrocyte-derived metabolites released from the hematoma contribute substantially to secondary brain injury after intracerebral hemorrhage (ICH), and enhancing endogenous hematoma clearance is a promising therapeutic strategy. Hexokinase 2 (HK2), a key glycolytic enzyme predominantly expressed in microglia, regulates microglial function, but its role in hematoma resolution after ICH remains unclear. We therefore investigated whether HK2 governs microglia/macrophage-mediated erythrophagocytosis and thereby influences hematoma clearance and neurological recovery after ICH. ICH was induced in male C57BL/6 mice by striatal collagenase injection, and HK2 was selectively inhibited with 3-bromopyruvate (3-BP). Neurobehavioral outcomes, hematoma volume, and hemoglobin content were quantified, and mechanisms were examined in hemoglobin- or erythrocyte-stimulated BV2 microglia and RAW 264.7 macrophages using pharmacological inhibition, glucose-6-phosphate (G-6-P) rescue, and lentiviral HK2 overexpression. After ICH, HK2 was localized predominantly to peri-hematomal microglia/macrophages, and nuclear HK2 increased progressively, peaking at 72 h. HK2 inhibition exacerbated neurological deficits, reduced M2-like (Arg-1⁺) microglia/macrophages, and delayed hematoma clearance without affecting initial hematoma formation. In vitro, G-6-P restored ATP levels suppressed by 3-BP but only partially rescued phagocytosis, indicating a non-glycolytic mechanism: HK2 upregulated peroxisome proliferator-activated receptor γ (PPARγ) and CD36, and pharmacological blockade of PPARγ abolished HK2-enhanced erythrophagocytosis. These findings identify HK2 as a contributor to endogenous hematoma clearance that promotes microglia/macrophage erythrophagocytosis at least in part through PPARγ/CD36 signaling, and support further genetic and cell-specific studies before HK2 is advanced as a therapeutic target for ICH.
In large-core ischemic stroke, outcomes after thrombectomy remain heterogeneous, and imaging markers that capture treatment-modifiable injury beyond lesion extent are needed. We investigated whether lesion water content on noncontrast CT, quantified as net water uptake (NWU), predicts 12-month functional outcome and modifies the effect of endovascular thrombectomy (EVT). This secondary analysis of the randomized TENSION trial included 198 patients with admission CT suitable for NWU quantification and available 12-month modified Rankin Scale (mRS) scores; 168 had paired 24-h CT for follow-up NWU (NWUFU) assessment. The primary outcome was ordinal 12-month mRS. Multivariable ordinal and logistic regression tested associations and the NWU × EVT interaction, with discrimination assessed by area under the receiver operating characteristic curve (AUC). Median baseline NWU was 16.4
Background: Ischemic stroke carries substantial residual risk despite acute revascularization and secondary prevention, and small-vessel disease (SVD) lacks specific preventive therapy. Mendelian randomization (MR) using cis-acting protein quantitative trait loci (pQTLs) identifies circulating proteins whose lifelong modulation alters stroke risk. Methods: We screened 589 conditionally independent cis-pQTLs from the INTERVAL study against four GIGASTROKE outcomes: any ischemic stroke (AIS), large-artery atherosclerosis (LAA), cardioembolic stroke (CES), and SVD. Wald ratio estimates were corrected by Benjamini-Hochberg false discovery rate (FDR) within each outcome, with a pooled cross-outcome correction as a sensitivity analysis. FDR-significant associations underwent colocalization (approximate Bayes factor; H4 > 0.80), replication in the independent deCODE pQTL cohort, cell-type expression validation in a human brain vascular single-nucleus atlas (65,479 nuclei), and phenome-wide safety screening. Results: Ten protein-outcome associations reached FDR < 0.05; nine replicated in deCODE and eight colocalized at H4 > 0.80, with two further pairs (ABO-LAA, cyclin H-CES) in the suggestive range (H4 0.70–0.80). For SVD, higher SPATA20 raised risk (OR 1.47, 95
Post-stroke depression (PSD) is a serious complication that significantly hinders stroke patients’ recovery and quality of life. Uncovering the molecular changes that drive PSD is vital for understanding how depression develops following a stroke. In this study, we established a reproducible PSD model using minimally invasive photochemical-induced focal cortical lesion. Transcriptomic sequencing demonstrated that dysregulation of circadian entrainment genes is a central pathway in the development of post-stroke depressive-like behaviors. Protein-protein interaction network analysis of these circadian rhythm-related genes identified six hub genes. Four of these, including Pomc and Bmp4, exhibited expression patterns consistent with experimental validation. Integrated single-cell transcriptomic analysis further pinpointed cell-type-specific expression abnormalities of Pomc in endothelial cells and Bmp4 in oligodendrocytes. Subsequently, in silico perturbation analysis further indicated that their shared underlying regulatory mechanisms involve cell adhesion and extracellular matrix interaction. Collectively, using transcriptomic and single-cell sequencing in a PSD model, this study revealed altered expression patterns of circadian rhythm-related genes, providing potential targets for further investigation into the pathogenesis of PSD.
The processes of clot formation and clot dissolution with fibrinolysis underpin the pathophysiological mechanisms of acute ischaemic stroke (AIS) and its treatment. Detailed understanding of the modulation of this system is required to develop effective and safe stroke therapeutics. Clot formation occurs with the interaction of the coagulation cascade, along with platelets and fibrin meshwork. Conversely, fibrinolysis involves the serine protease plasmin, its zymogen, plasminogen and its enzymatic conversion by tissue plasminogen activator. The regulators and inhibitors that modulate the interactions in clot formation and fibrinolysis can be potential targets for new and emerging stroke therapies. The aim of this narrative review is to help inform stroke clinicians and researchers about the role of the fibrinolytic system and its inhibitors in AIS and the potential for new therapeutic targets. We outline the processes involved in clot formation and dissolution, the role of endogenous inhibitors of the fibrinolytic system, followed by potential therapeutic targets including tissue plasminogen activators as well as novel therapies and adjuncts. Better understanding of these processes will provide insight into the variable response to current stroke fibrinolytics amongst AIS patients and help to develop new and improved AIS therapeutics in future.
