Glycolysis

Ischemic stroke, a leading cause of global disability and mortality, remains inadequately treated beyond reperfusion, with persistent translational failures in neuroprotection. We posit metabolic reprogramming in ischemic stroke (MRIS) as the unifying pathophysiological driver, where acute compensatory glycolysis collides with enzymatic lipid peroxidation to ignite neuroinflammation and early deficits. This metabolic crisis transcends neuron-centric models, integrating single-cell heterogeneity with bidirectional brain-peripheral crosstalk: hepatic ketogenesis releases neuroprotective β-hydroxybutyrate; adipose lipolysis fuels inflammatory storms; and gut dysbiosis disrupts barrier integrity, amplifying neuroinflammation. MRIS progresses through temporally stratified phases. An acute glycolytic-excitotoxic crisis and nicotinamide adenine dinucleotide (NAD+) depletion trigger neuroimmune dysfunction. Subacute lipid peroxidation cascades trigger ferroptosis and microglial polarization, whereas chronic-phase recovery of executive networks is scaffolded by sirtuin-mediated mitochondrial biogenesis and the interplay between adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR). Spatial metabolomics and single-cell omics decode cell-type-specific vulnerabilities, revealing astrocytic lipid droplets, microglial succinate accumulation, and neuron-glia lactate shuttles as targetable nodes. Chronobiology further dictates therapeutic windows: lactate dehydrogenase A (LDHA) inhibition mitigates hyperacute acidosis, while NAD+ salvage pathways optimize chronic mitochondrial plasticity. We propose that metabolic reprogramming is a central amplifier of both ischemic injury and recovery, linking cerebral vascular occlusion to systemic organ dysfunction. By reframing stroke within a vascular-metabolic continuum, MRIS shifts the paradigm from a neuron-centric view to one of systemic bioenergetic failure, accounting for past translational gaps and opening pathways for precision therapies, from pentose phosphate pathway modulation to nanoparticle-based metabolite delivery and microbiome interventions. In this framework, metabolic plasticity becomes not just a consequence but a therapeutic target, transforming stroke from an untreatable vascular event to a modifiable metabolic disorder.

Glycolysis activation plays a critical role in sustaining the proinflammatory phenotype of macrophages, which is key to initiating and advancing liver fibrosis. However, the underlying mechanisms that trigger glycolytic activation and their contribution to inflammation remain poorly understood. In this study, we showed that inhibiting glycolysis markedly suppresses macrophage M1 polarization and alleviates liver inflammation and fibrosis, whereas enhancing glycolysis in hepatic macrophages produces the opposite effect. Additionally, our results demonstrated that glycolytic flux is necessary for activation of the STING/TBK1/IRF3 pathway. Moreover, STING activation was found to reciprocally stimulate glycolysis in macrophages. Mechanistically, we found that ATP generated through glycolysis promotes STING pathway activation and enhances the interferon-dependent immune response. Moreover, activation of IRF3, a downstream transcription factor of STING, upregulates HIF-1α transcription, further driving glycolysis. These findings uncover novel mechanistic links between STING signaling and glycolytic metabolism, emphasizing their coordinated role in promoting macrophage M1 polarization. Together, our data suggest that targeting the interaction between metabolic reprogramming and immune signaling offers an effective therapeutic approach for treating liver fibrosis and cirrhosis.

BackgroundMicroglia, the resident immune cells of the central nervous system (CNS), play pivotal roles in the onset and progression of various neurological disorders. Owing to their remarkable plasticity, microglia can adopt diverse phenotypic states in response to distinct microenvironmental cues. Over the past decades, accumulating evidence has demonstrated that immune cell metabolism critically regulates their polarization and effector functions through a process termed metabolic reprogramming, in which glucose metabolism is particularly central. Glycolytic reprogramming underlies the entire polarization process, and elucidating its mechanisms may enable targeted modulation of microglial activity to mitigate their deleterious effects in CNS pathologies, thereby offering novel therapeutic avenues for these diseases.Aim of the reviewThis paper summarizes what is known about microglial polarization and glycolytic reprogramming and explores their important roles in the development of neurological diseases. The link between microglial metabolomics and epigenetics in neurological disorders requires further study.Key scientific concepts of the reviewMicroglia exhibit distinct phenotypic states at different stages of central nervous system (CNS) disorders, and these polarization processes are closely coupled with glucose metabolic reprogramming. Proinflammatory microglia predominantly rely on glycolysis, whereas reparative or anti-inflammatory phenotypes primarily utilize oxidative phosphorylation. Targeting glycolytic pathways to limit the polarization of microglia toward proinflammatory states has emerged as a promising therapeutic strategy for CNS diseases.

Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach-including metabolomics, proteomics, and lipidomics-was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.