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.

Somatosensory-vagal reflexes evoked by electroacupuncture (EA) can modulate visceral functions. However, the underlying principles and neural mechanisms remain poorly understood, hindering further optimization. Here, we identified key neural components essential for EA topographically driving the somatosensory-vagal-gastric reflex in mice. EA drove this reflex via activation of a subset of transient receptor potential vanilloid-1 (TRPV1)⁺ nociceptors marked by the expression of Adra2a and located exclusively in deep fascial tissues. Through TRPV1⁺ fibers, EA activated a subtype of gastro-projecting Oxtr⁺ fibers originating from the dorsal motor nucleus of the vagus (DMV). Genetic ablation of TRPV1⁺ fibers or Oxtr⁺ DMV neurons attenuated EA-induced gastric reflexes. Conversely, optogenetic activation of these neurons was sufficient to drive gastric motility in mice. Using similar stimulation parameters, we demonstrated that EA successfully improved gastric functions in patients with dysmotility-like functional dyspepsia (chictr.org.cn: ChiCTR2300072636). Our findings thus provide a neural anatomical basis for EA topographically to promote and treat gastric motility disorders.

Stroke remains a leading cause of death and disability worldwide, and electroacupuncture has a long history of use in stroke treatment. This meta-analysis and systematic review aimed to evaluate the efficacy of electroacupuncture and explore its potential mechanisms in animal models of ischemic stroke. The PubMed, EMBASE, Web of Science, CENTRAL, and CINAHL databases were comprehensively searched up to May 1, 2024. This review included articles on preclinical investigations of the efficacy and mechanisms of electroacupuncture in treating ischemic stroke. Data from 70 eligible studies were analyzed in Stata 18.0, using a random-effects model to calculate the standardized mean difference (Hedge’s g). The risk of bias was assessed using RevMan 5.4 software, and the quality of evidence was rated according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Subgroup analyses were conducted to test the consistency of the results and sensitivity analyses were used to assess their robustness. The quality assessment revealed that most studies adequately handled incomplete data and selective reporting. However, several methodological limitations were identified: only 4 studies demonstrated a low risk of allocation concealment, 26 achieved a low risk of outcome assessment bias, and 9 had a high risk of randomization bias. Additionally, there was an unclear risk regarding participant blinding and other methodological aspects. The GRADE assessment rated 12 outcomes as moderate quality and 6 as low quality. The mechanisms of electroacupuncture treatment for ischemic stroke can be categorized as five primary pathways: (1) Electroacupuncture significantly reduced infarct volume and apoptotic cell death ( P < 0.01) in ischemic stroke models; (2) electroacupuncture significantly decreased the levels of pro-inflammatory factors ( P < 0.01) while increasing the levels of anti-inflammatory factors ( P = 0.02); (3) electroacupuncture reduced the levels of oxidative stress indicators ( P < 0.01) and enhanced the expression of antioxidant enzymes ( P < 0.01); (4) electroacupuncture significantly promoted nerve regeneration ( P < 0.01); and (5) electroacupuncture influenced blood flow remodeling ( P < 0.01) and angiogenesis ( P < 0.01). Subgroup analyses indicated that electroacupuncture was most effective in the transient middle cerebral artery occlusion model ( P < 0.01) and in post-middle cerebral artery occlusion intervention ( P < 0.01). Dispersive waves were found to outperform continuous waves with respect to neuroprotection and anti-inflammatory effects ( P < 0.01), while scalp acupoints demonstrated greater efficacy than body acupoints ( P < 0.01). The heterogeneity among the included studies was minimal, and sensitivity analyses indicated stable results. Their methodological quality was generally satisfactory. In conclusion, electroacupuncture is effective in treating cerebral ischemia by modulating cell apoptosis, oxidative stress, inflammation, stroke-induced nerve regeneration, blood flow remodeling, and angiogenesis. The efficacy of electroacupuncture may be influenced by factors such as the middle cerebral artery occlusion model, the timing of intervention onset, waveform, and acupoint selection. Despite the moderate to low quality of evidence, these findings suggest that electroacupuncture has clinical potential for improving outcomes in ischemic stroke.

Objective: Recent studies have shown that irisin, a novel peptide hormone derived from muscles, could be used as a potential therapeutic drug against ischemic stroke. Moreover, electroacupuncture (EA) is widely used in the treatment of ischemic stroke. Yet, whether irisin is involved in the EA neuroprotection remains unclear. The following study investigated the association between serum and peri-lesional cortex irisin and EA-induced post-stroke motor recovery in rats. Methods: The middle cerebral artery occlusion (MCAO) method was used to induce ischemic stroke in rats. Rats were randomly divided into two groups: a middle cerebral artery occlusion (MCAO) group (MCAO rats without treatment) and an electroacupuncture (EA) group (MCAO rats treated with EA). On the 3rd day post-stroke, infarct volume, behavioral deficits, surviving neurons, irisin protein expression in peri-infarction cortex, muscle tissue, and serum were evaluated to identify the neuroprotective of EA in acute ischemic stroke. Results: Compared with the MCAO group, the EA group showed better behavioral performance, a smaller cerebral infarct volume, more surviving neurons, and a significant increase in irisin expression in the peri-infarction cortex and serum (p< 0.05). However, no difference in irisin expression in the muscle tissue was found between the MCAO group and the EA group (p> 0.05). Conclusion: EA promotes motor function recovery, reduces the volume of cerebral infarction, and alleviates neuronal death following ischemic stroke by enhancing the expression of irisin in both the blood and peri-lesional cortex.

Stroke significantly impacts mortality and long-term disability, necessitating effective rehabilitation strategies to enhance recovery. This review examines the roles of vagus nerve stimulation (VNS) and fastigial nucleus stimulation (FNS) in facilitating ischemic stroke recovery through brain-body interactions. VNS enhances ischemic stroke recovery by reprogramming microglia from proinflammatory (M1) to neuroprotective (M2) phenotypes, reducing neuroinflammation and promoting tissue repair via neurotrophic factors. It has shown promise in clinically improving chronic upper limb deficits when combined with rehabilitation therapies. Conversely, FNS provides cerebellar-mediated neuroprotection by mainly mitigating excitotoxic damage and inflammatory responses independent of cerebral blood flow alterations, as evidenced by preclinical models of middle cerebral artery occlusion. By integrating VNS-driven immunomodulation with FNS-mediated excitotoxicity suppression, this review highlights their synergistic potential to improve rehabilitation outcomes for ischemic stroke survivors. Biomarker-guided protocols: VNS for cortical/subcortical ischemic deficits and FNS for cerebellar network recovery are advocated to address postischemic disability via anti-inflammatory rewiring, neuroplasticity enhancement, and cerebellar-thalamocortical circuit stabilization. Critical gaps remain in hemorrhagic stroke, where FNS’s excitotoxicity suppression may destabilize clots, necessitating subtype-specific safety validations.

This study aimed to explore the cumulative effects and expression patterns of electroacupuncture (EA) on irisin secretion, observe the effects of EA on the recovery of neurobehavioral function and vascular remodeling after cerebral ischemia, and elucidate the mechanism by which EA promotes vascular remodeling by regulating irisin expression. A rat model of left middle cerebral artery occlusion (MCAO) was prepared, and EA was performed. Tissue distribution and expression of irisin were determined by immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Western blotting. Type III fibronectin domain protein 5-silenced adeno-associated virus (rAAV-shFNDC5) was injected into the lateral ventricle as a control. Neurobehavioral function was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining and behavioral experiments, while vascular remodeling was evaluated using laser speckle blood flow imaging, and the expressions of irisin and vascular remodeling-related factors were measured by ELISA and Western blotting. The number of FNDC5-positive neurons, fluorescence intensity, and irisin expression reached their maximum increase after 7 days of EA treatment. In addition, the EA group exhibited a significant reduction in cerebral infarct volume and impairment of neurobehavioral function, an increase in cerebral blood flow and microvascular diameter on the ischemic side, and significantly higher expression levels of FNDC5, brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS). However, rAAV-shFNDC5 significantly weakened the therapeutic effects of EA. EA upregulated irisin expression, reaching a peak after 7 days of EA and then stabilizing. EA facilitated vascular remodeling after cerebral ischemia, and this might be associated with the activation of the irisin-mediated VEGF/Akt/eNOS signaling pathway.