Understanding Metabolic Changes in Ischemic Stroke

Ischemic stroke triggers a cascade of excitotoxic and metabolic failures that critically disrupt neuronal energetics. Central to this cascade is glutamate-induced hyperactivation of N-methyl-D-aspartate receptors (NMDA receptors), driving pathological calcium influx that overwhelms mitochondrial buffering capacity [103] (Fig. 1). This ion imbalance uncouples oxidative phosphorylation, depleting ATP and impairing Na⁺/K⁺-ATPase function. Consequently, membrane depolarization intensifies, facilitating further glutamate release and establishing a self-perpetuating cycle of excitotoxicity [104]. Simultaneously, delayed sodium channel inactivation and impaired potassium repolarization exacerbate calcium overload, accelerating metabolic collapse.

Mitochondrial dysfunction amplifies reactive oxygen species (ROS) production, inducing DNA damage and hyperactivating PARP-1 [105]. PARP-1 hyperactivation depletes cytosolic NAD⁺, a central redox cofactor essential for glycolysis and TCA cycle function, precipitating bioenergetic failure. This NAD⁺ deficit directly impairs sirtuin activity (SIRT), compromising their regulation of mitochondrial biogenesis via PGC-1α, antioxidant defense through FOXO transcription factors, and metabolic adaptation via HIF-1α modulation [106, 107]. Although neurons activate compensatory NAD⁺ salvage through nicotinamide phosphoribosyltransferase (NAMPT) [108], this pathway fails to offset PARP-1-driven NAD⁺ catabolism during stroke [106], resulting in sustained sirtuin suppression and disrupted mitochondrial dynamics. Consequently, the NAD⁺/NADH imbalance propagates metabolic inflexibility, impairing neuron-glia metabolic crosstalk while dysregulating the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD)/kynurenine pathway, a critical alternate NAD⁺ biosynthesis route [109, 110]. Critically, acute AMPK activation during ATP depletion exacerbates glycolytic overdrive and FAO, while chronic mTORC1 signaling in surviving neurons drives maladaptive lipid synthesis that fuels ferroptosis [111]. Metabolic disruption also extends to thrombotic mechanisms: platelet activation requires a glycolytic ATP surge mediated by HK2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), while hyperglycemia stiffens clots via advanced glycation end-product (AGE) crosslinking. As a result, thrombectomy alone is insufficient if these metabolic drivers persist, underscoring the need for metabolic co-interventions alongside mechanical reperfusion.

Preclinical studies have suggested that inhibiting PARP-1 or supplementing NAD⁺ could offer neuroprotective benefits [112]. However, translating these strategies into clinical practice remains challenging due to potential off-target effects and limitations in crossing the BBB. Additionally, emerging evidence suggests that NAD⁺ precursors, such as nicotinamide riboside, may help alleviate post-stroke cognitive deficits by restoring synaptic plasticity [106, 113]. The complex interplay among glutamate excitotoxicity, mitochondrial collapse, and NAD⁺ dysregulation characterizes the disruption of neuronal energetics in strokes. Therapeutic approaches targeting these pathways with glutamate receptor antagonists, PARP-1 inhibitors, or NAD⁺ enhancers are promising for breaking the cycle of metabolic failure. However, the therapeutic windows for effective intervention remain narrow, emphasizing the need for refined strategies that also address thrombo-metabolic convergence.

Astrocytes exemplify MRIS's spatiotemporal duality: their early glycolytic support later evolves into lipid-driven neuroinflammation. This shift directly impacts microglial behavior, where succinate accumulation triggers inflammatory cascades, highlighting how MRIS propagates injury across cell types [114]. Acute ischemia initiates glycogenolysis in astrocytes, releasing glucose-6-phosphate that fuels glycolysis and lactate production [97, 102]. This astrocyte-neuron lactate shuttle initially sustains neuronal ATP synthesis; however, as lactate accumulates, it leads to acidosis and an increase in ROS, ultimately becoming detrimental to neuronal health [115] (Fig. 1). Prolonged glycolysis depletes astrocytic glycogen reserves, prompting a metabolic shift toward FAO and the accumulation of lipid droplets (LDs) [116]. Once regarded as inert storage depots, LDs are now recognized as active immunometabolic hubs that sequester toxic lipids and release pro-inflammatory mediators, including prostaglandin E2 (PGE2) [117, 118].

The metabolic landscape of astrocytes is further complicated by HIF-1α, which upregulates pyruvate dehydrogenase kinase (PDK) [6]. This action diverts pyruvate from the TCA cycle, funneling it instead toward lactate production. While this pseudo-hypoxic state may provide short-term adaptive benefits, it ultimately impairs mitochondrial respiration and heightens oxidative stress [119]. Recent advances in single-cell RNA sequencing have identified subpopulations of "lipid-laden astrocytes" that express LD-associated proteins, such as PLIN2, alongside pro-inflammatory cytokines [120]. Notably, the presence of these astrocyte subpopulations correlates with poorer outcomes in murine models of stroke. The dual nature of astrocytic metabolism to balance neuroprotective lactate shuttling with pro-inflammatory lipid signaling underscores the importance of temporally precise therapeutic interventions. Pharmacological inhibition of LDs formation through DGAT inhibitors or modulation of HIF-1α activity may mitigate chronic neuroinflammation without compromising acute energetic support [90, 98, 99].

The cerebral microvasculature is both a victim and amplifier of metabolic dysfunction in stroke. Endothelial cells, reliant on glycolysis under normoxia, switch to FAO during ischemia, driven by HIF-2α upregulation of carnitine palmitoyltransferase 1A (CPT1A) [121]. While FAO sustains ATP production, it generates excess acetyl-CoA, inhibiting pyruvate dehydrogenase and exacerbating lactate accumulation. This metabolic shift also reduces nitric oxide (NO) bioavailability, impairing vasodilation and promoting thrombus formation.

Pericytes, contractile mural cells regulating capillary tone, exhibit HIF-1α-mediated RhoA (Ras homolog gene family, member A)/Rho-associated protein kinase (ROCK) pathway activation, leading to sustained contraction and capillary "no-reflow" post-recanalization [122]. Pericyte contraction, initially hemodynamic, is fueled by astrocyte-derived lactate activating acid-sensing ion channels (ASICs), positioning metabolic modulation via LDHA inhibition as a potential strategy to rescue perfusion [123]. Furthermore, pericyte-derived inflammatory mediators such as IL-6 recruit neutrophils, exacerbating BBB disruption. Therapeutic strategies targeting microvascular metabolism include CPT1A inhibitors to normalize endothelial bioenergetics and ROCK inhibitors like fasudil to alleviate pericyte constriction [124, 125]. Notably, HIF stabilization agents like roxadustat show dual benefits, enhancing endothelial cells' resilience while suppressing pericyte hyperactivation in preclinical models [126]. However, balancing these interventions to avoid off-target effects on angiogenesis remains critical. MRIS does not explain why vascular occlusion occurs but reveals how its consequences propagate systemically. Stroke remains etiologically heterogeneous, ranging from cardioembolic to lacunar causes, with MRIS serving as a common downstream amplifier of injury.

Pre-existing vascular diseases accompanied by metabolic sequelae profoundly exacerbate MRIS by hijacking its core pathways, creating vicious cycles that amplify ischemic injury. In metabolic dysfunction-associated steatotic liver disease, impaired hepatic ketogenesis reduces circulating β-hydroxybutyrate (BHB), depriving neurons of a neuroprotective fuel and worsening energy failure. Rodents with hepatic steatosis develop 40% larger infarcts due to defective ketogenesis, a deficit reversible with BHB supplementation [127, 128]. Obesity primes adipose NLRP3 inflammasomes, elevating systemic free fatty acids (FFAs) and IL-1β that intensify cerebral lipid peroxidation. Clinically, body mass index (BMI > 30) correlates with 2.5× higher cerebrospinal fluid (CSF) IL-1β and larger peri-infarct lipid peroxide deposits [19].

Diabetic hyperglycemia triggers paradoxical glycolysis suppression despite energy deficits, while microglial advanced glycation end products (RAGE) receptors, a dual insult exacerbating acidosis and neuroinflammation, are evidenced by diabetics exhibiting 3× higher lactate/penumbra volume ratios than non-diabetics [46, 129]. Hypertension, conversely, upregulates endothelial FAO, reducing nitric oxide bioavailability and capillary perfusion, explaining why hypertensives gain 50% less reperfusion benefit post-thrombectomy [122, 130, 131]. These comorbidities converge on mitochondrial ROS overproduction and NLRP3-driven neuroinflammation. Diabetic hyperglycemia further exacerbates this by suppressing astrocytic pentose phosphate pathway flux, which depletes nicotinamide adenine dinucleotide phosphate (NADPH) reserves [132, 133], a mechanism that mirrors defects in diabetic neuropathy where impaired redox defense amplifies oxidative injury. This metabolic synergy is illustrated by the case of a 65-year-old diabetic woman with a BMI of 34 and apolipoprotein E 4 (APOE4) genotype, presenting with cardioembolic stroke [47]. Her personalized MRIS intervention was tailored to address specific vulnerabilities identified through stratification, including elevated TMAO levels indicative of gut dysbiosis, low β-hydroxybutyrate reflecting impaired diabetic ketogenesis, and high low-density lipoprotein linked to an APOE4-driven lipid efflux defect [120]. Consequently, metformin was withheld due to the risk of lactic acidosis, and ketogenic therapy was avoided, given APOE4-associated lipid sensitivity [120, 132]. Targeted therapeutics included a TMA lyase inhibitor, Akkermansia probiotic supplementation, and low-dose rosuvastatin. This phenotype-specific modulation of MRIS resulted in a 45% reduction in infarct growth at 72 h (magnetic resonance imaging-diffusion weighted imaging, DWI) compared to standard care, validating the approach [13, 28]. Importantly, this convergence of comorbidities helps explain broader divergences in stroke outcomes: the same MRIS pathway, such as the glycolytic surge that drives lipid peroxidation in obesity, also accelerates endothelial dysfunction in hypertension, underscoring the critical need for precision stratification and tailored interventions.

During ischemic stroke, hypoxia and glucose deprivation compel cells to transition from oxidative phosphorylation to anaerobic glycolysis [115, 133, 134]. While glycolysis provides a rapid ATP source, its low ATP yield drives intracellular lactate accumulation. Critically, lactate exhibits concentration-dependent duality: at <5 mM, it stabilizes HIF-1α to promote anti-inflammatory microglial M2 polarization and serves as an alternative neuronal fuel; however, at >5 mM, it induces acidosis, inactivates pH-sensitive enzymes, and activates apoptotic signaling pathways [135] (Fig. 1)

Furthermore, lactate stabilizes HIF-1α, which in turn promotes the expression of vascular endothelial growth factor [135]. This action disrupts the integrity of the BBB, increasing its permeability. In microglial BV2 cells subjected to oxygen-glucose deprivation, lactate has been shown to upregulate the chemokine Chemokine (C-C motif) ligand 7 (CCL7) through HIF-1α signaling. Post-reperfusion, regions surrounding the infarct show elevated CCL7 expression, and inhibition of HIF-1α reverses lactate-induced neuroinflammation and infarct expansion [136]. The administration of recombinant CCL7 counteracts the neuroprotective effects of lactate, highlighting the critical role of the HIF-1α–CCL7 axis in modulating neuroinflammatory responses following stroke. Microglial pro-inflammatory polarization is further sustained by altered potassium (KCNJ2, potassium inwardly rectifying channel subfamily J member 2) and calcium (TRPM2, transient receptor potential melastatin 2) channel activity, which regulate cytokine release and immune activation.

The brain's dependence on oxidative phosphorylation renders it susceptible to energy failures during ischemia. The depletion of ATP impairs the maintenance of ion gradients, resulting in membrane depolarization in both neurons and glial cells [137] (Fig. 1). This depolarization activates voltage-gated calcium channels, leading to excessive glutamate release into the extracellular space. Concurrently, the failure of energy-dependent glutamate reuptake mechanisms exacerbates extracellular glutamate levels.

The resulting glutamate overstimulation of NMDA and metabotropic glutamate receptors (mGluRs) further complicates the situation, whereby mGluR activation via phospholipase C (PLC) and inositol trisphosphate (IP₃) signaling prompts Ca²⁺ overload [138]. Moreover, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated Na⁺/Cl⁻ influx further disturbs osmotic balance, contributing to cytotoxic edema, a process blocked by AMPA antagonists (e.g., perampanel) in rodent models [139, 140]. This edema is detrimental, compromising perfusion in peri-infarct regions, elevating intracranial pressure, and increasing the risk of herniation, an important factor contributing to early mortality. Imaging modalities such as magnetic resonance imaging and computed tomography are essential for monitoring edema during acute stroke management.

Ischemic stroke incites profound alterations in amino acid metabolism. The excessive accumulation of excitatory neurotransmitters, particularly glutamate, drives excitotoxicity, while metabolites such as arginine regulate inflammatory responses through NO synthesis and urea cycle modulation. Recent studies position amino acid metabolism as an increasingly important therapeutic target in stroke [141 –143] (Table S2).

Interestingly, the small-molecule amino acid (AA)-147, which activates the unfolded protein response transcription factor activating transcription factor 6 (ATF6), protects against glutamate-induced toxicity by covalently modifying KEAP1, thereby activating NRF2-dependent antioxidant pathways [146]. However, sustained NMDA receptor activation can reverse the cystine/glutamate antiporter transporter's action, leading to intracellular glutathione depletion and amplifying oxidative damage [147 –149].

In the healthy brain, neurons and astrocytes sustain a delicate metabolic symbiosis through the glutamate–glutamine cycle, a lifeline where neurons convert astrocyte-derived glutamine into glutamate for neurotransmission, while astrocytes rapidly clear synaptic glutamate via excitatory amino acid transporters (EAAT1/2), detoxify it to glutamine via glutamine synthetase, and return this precursor to neurons to sustain synaptic function [150] (Fig. 2a). This elegant partnership unravels catastrophically during ischemic stroke. Surging neuronal glutamate release overwhelms astrocytic uptake capacity, flooding the extracellular space with excitotoxic glutamate. Compounded by astrocytic EAAT dysfunction, the cycle collapses, triggering a metabolic emergency. Under physiological conditions, neurons import glutamine via sodium-coupled neutral amino acid transporter 3 (SNAT3), converting it to glutamate via glutaminase for synaptic release through vesicular glutamate transporters (VGLUTs). Astrocytes clear excess glutamate via EAAT, convert it to glutamine via glutamine synthetase, and shuttle glutamine back [151] via SNAT2/3. Ischemic stroke disrupts this cycle: SNAT dysfunction impairs glutamine supply, while VGLUT hyperactivity and EAAT failure exacerbate extracellular glutamate accumulation. Astrocytes, now forced into anaerobic glycolysis, overproduce lactate [152], a metabolite with context-dependent roles. Through MCT-mediated transport, elevated lactate lowers extracellular pH, stabilizing HIF-1α in microglia. This HIF-1α activation suppresses chemokine CCL7, inhibiting NF-κB and reducing pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-6, thereby promoting anti-inflammatory M2 polarization. Paradoxically, in early ischemia, lactate overabundance fuels a pro-inflammatory M1-dominant milieu [153]. These activated microglia unleash ROS and IL-1β, compromising BBB integrity and recruiting peripheral immune cells (Fig. 2b).

Amid this chaos, astrocytes diverge into functionally opposing phenotypes: cytotoxic A1-reactive astrocytes secrete MMP-9 and ROS, actively eroding the neurovascular unit, while reparative A2 astrocytes deploy Wnt/β-catenin signaling and TLR4-mediated neurotrophin release to facilitate synaptic rewiring and functional reorganization [154, 155]. The astrocyte-neuron lactate shuttle, once a routine energy exchange, becomes a critical survival mechanism. Astrocyte-derived lactate, shuttled via MCT, sustains neuronal mitochondrial respiration during glucose deprivation, while oligodendrocytes extend this metabolic lifeline to axons, preserving ionic gradients and axonal integrity [152]. However, this adaptation is perilously double-edged. Lactate accumulation acidifies the microenvironment, exacerbating ion dyshomeostasis and attracting neutrophil extracellular traps, web-like DNA structures that entangle MMP-9, amplifying BBB leakage [156] (Fig. 2c). Regulatory T cells counterbalance this damage, modulating MMP-9 activity to stabilize the barrier, but their delayed recruitment often cedes ground to early inflammatory cascades.

The ischemic brain thus embodies a metabolic paradox: accelerated glycolysis provides immediate ATP but promotes long-term injury through acidosis and oxidative stress; lactate shifts from neuroprotective fuel to pro-inflammatory mediator as concentrations exceed 5 mM; and astrocytes transition from neurosupportive roles of sustaining neuronal energetics via lactate shuttling to neurotoxic contributors through chronic lipid droplet accumulation that exacerbates neuroinflammation. Reconciling these roles demands precision, targeting the timing and spatial distribution of lactate flux, restoring glutamate–glutamine cycle fidelity, or harnessing A2 astrocyte plasticity. As we dissect this metabolic tango, the goal is clear: to transform the post-stroke brain from a battlefield of competing signals into a scaffold for rebirth, where neuron–astrocyte crosstalk is not merely salvaged but strategically rewired.

The process of reperfusion intensifies ROS generation, overwhelming the brain's antioxidant defenses, such as superoxide dismutase and glutathione peroxidase. This oxidative stress leads to lipid peroxidation, protein oxidation, and mitochondrial DNA damage. Mitochondrial pyruvate oxidation generates citrate, which is exported to the cytoplasm via ATP-citrate lyase for acetyl-CoA production, fueling lipid synthesis and protein acetylation [166]. Accumulation of saturated fatty acids (SFAs) such as palmitate [C16:0], and stearate [C18:0] disrupts mitochondrial dynamics, impairing motility and ATP synthesis while promoting ROS generation [167]. ROS are also responsible for disrupting mitochondrial calcium homeostasis, a process mediated by voltage-dependent anion channels and the mitochondrial calcium uniporter [168]. Elevated calcium levels within the mitochondrial matrix can depolarize the mitochondrial membrane potential (ΔΨm), resulting in the opening of the mPTP [169]. The opening of mPTP, which is regulated by adenine nucleotide translocase and cyclophilin D, facilitates the release of pro-apoptotic factors, including cytochrome c and apoptosis-inducing factors, into the cytosol. Cytochrome c activates caspase-9 through apoptosome formation, culminating in the activation of caspase-3 and subsequent PARP-mediated DNA damage. These cascades dramatically enhance neuronal loss through apoptosis and necroptosis.

Ischemic glutamate receptor hyperactivation stimulates phosphatidylinositol-specific PLC, cleaving PIP₂ into IP₃ and diacylglycerol (DAG). IP₃ then triggers calcium release from endoplasmic reticulum stores, exacerbating intracellular calcium overload. DAG and free fatty acids (e.g., arachidonic acid) are metabolized by cyclooxygenase (COX) and LOX into pro-inflammatory eicosanoids (prostaglandins, leukotrienes), amplifying neuroinflammation [174, 175]. Enzymes like DGAT, PCYT1, and ATGL further accelerate aberrant lipid turnover, promoting membrane destabilization. Elevated BMI (>30) exacerbates these pathways through dual mechanisms: Adipose-derived leptin resistance elevates systemic free fatty acids, fueling neuronal lipid peroxidation; and peroxisome proliferator-activated receptor (PPAR)-γ dysfunction in obese microglia amplifies pro-inflammatory eicosanoid synthesis (e.g., PGE₂). Human lipidomics studies confirm that high BMI correlates with elevated 4-hydroxynonenal (4-HNE), a lipid peroxidation marker, in post-stroke patients [176]. Preclinical models corroborate this, showing 40% larger infarct volumes in high-fat-diet mice with increased astrocytic lipid droplet accumulation [175].

Glutamate excitotoxicity strains this system by activating mGluR receptors, driving PLC-mediated PIP2 hydrolysis into DAG and IP₃ (Fig. 4b) [174]. This initiates acute lipid reprogramming where phospholipase A2 activation releases free fatty acids and lysophospholipids, triggering rapid membrane destabilization and inflammatory signaling. The resulting reactive oxygen species and cytotoxic aldehydes (e.g., 4-HNE) disrupt ion homeostasis, accelerating subacute ferroptosis through enhanced ALOX15-dependent peroxidation of polyunsaturated fatty acids. Paradoxically, while lipids drive toxicity, they simultaneously enable repair: astrocytes and microglia scavenge lipids to buffer damage, while chronic Lipin-1-mediated membrane repair mechanisms support phospholipid remodeling and structural recovery.

Ischemic stroke thus unveils competing metabolic adaptations where glycolytic overdrive and lipid dysregulation converge, a storm that both devastates and drives recovery. Therapeutic promise lies in phase-specific interventions: targeting acute lipid droplet dynamics, fine-tuning subacute SFA balance to counter ALOX15/GPX4-dependent peroxidation, which propagates membrane damage via Fenton chemistry, or intercepting pro-inflammatory mediators [177, 178]. As single-cell analyses confirm ferroptosis through ACSL4 upregulation and mitochondrial shrinkage [179, 180], the challenge remains to harness lipid metabolism's regenerative capacity while suppressing peroxidation cascades, thereby advancing targeted neural repair strategies.

Lactate, traditionally viewed as a metabolic byproduct, emerges as a critical modulator of neuroinflammation and neuroprotection post-stroke. Experimental studies demonstrate that L-lactate administration (100 mM, 2 µL) into the cerebral ventricles 30 min post-MCAO reduces infarct volume, neuronal apoptosis, and functional deficits [181]. Mechanistically, lactate stabilizes HIF-1α, repressing pro-inflammatory microglial markers such as a cluster of differentiation (CD)-86, inducible nitric oxide synthase (iNOS), IL-6, and NF-α while enhancing anti-inflammatory mediators such as arginase-1, CD206, Chitinase 3-like 3 (Chi3l3, a marker for anti-inflammatory M2 microglia/macrophages), transforming growth factor (TGF)-β, and IL-10 via NF-κB suppression [182] (Fig. 2b). Transcriptomic profiling in oxygen-glucose deprivation-treated BV2 microglia identifies CCL7 as a lactate-responsive chemokine. Recombinant CCL7 administration reverses lactate's neuroprotective effects, confirming the HIF-1α–CCL7 axis as central to lactate-mediated immunomodulation [136]. Lactate accumulation lowers extracellular pH, thereby stabilizing HIF-1α in microglia. This stabilization suppresses CCL7 expression, which in turn inhibits NF-κB activation, silencing TNF-α and IL-6 production while promoting anti-inflammatory M2 polarization. This process is amplified by systemic lipid mediators: Adipose-derived FFAs cross the compromised BBB, fueling lipid peroxidation and NLRP3 inflammasome activation [50]. Gut-derived TMAO heightens platelet reactivity and cerebral thrombosis, synergizing with lactate to exacerbate neuroinflammation [183]. Microglial pro-inflammatory polarization is further sustained by dysregulated potassium (KCNJ2) and calcium (TRPM2) channels, creating a vicious cycle of cytokine release and immune activation.

In ischemic stroke, surviving cells confront a metabolic paradox: generating ATP while defending against oxidative catastrophe and rebuilding macromolecules. The pentose phosphate pathway (PPP) transitions from a routine metabolic route to a critical orchestrator of survival [184]. Post-stroke, proliferating neurons and glia adopt a Warburg-like metabolic shift, prioritizing glycolysis over oxidative phosphorylation to rapidly harvest ATP and funnel intermediates into the PPP, a strategy more commonly associated with cancer cells [185]. This reprogramming is not merely an energy grab but a calculated survival tactic. The PPP's first arm generates NADPH, the lifeblood of antioxidant defense, which resuscitates glutathione to neutralize the deluge of ROS unleashed by ischemia. Simultaneously, its second arm synthesizes ribose-5-phosphate, the backbone of nucleotides required for DNA repair and the proliferation of repair-oriented cells, from neural progenitors to endothelial cells rebuilding damaged vasculature.

Key enzymes like glucose-6-phosphate dehydrogenase surge in neurons, sustaining redox balance when mitochondrial TCA cycling fails [186]. Glycolysis regenerates NAD⁺ while feeding the PPP and serine/glycine one-carbon metabolism, enabling nucleotide synthesis and epigenetic adaptations. However, this lifeline diverts glucose from ATP production, escalating reliance on anaerobic glycolysis and acidosis risk. Critically, the PPP intersects with systemic inflammation. Amid lipid peroxidation cascades ("lipid storms"), adipose-derived free fatty acids and gut-generated TMAO amplify neuroinflammation and thrombosis [183] (Table S3). The PPP thus becomes a nexus where energy crisis, oxidative stress, and lipid toxicity converge. Targeting PPP flux through NADPH synthesis to quench peroxidation or nucleotide tuning could tip recovery balances, but precision is vital to avoid exacerbating metabolic exhaustion.

Amidst the "lipid storm" of peroxidation and membrane breakdown, the PPP's role transcends mere intermediary metabolism. It becomes a nexus where energy crisis, oxidative stress, and regenerative demand converge, offering both hope and vulnerability. Targeting PPP flux, enhancing NADPH synthesis to quench lipid peroxidation, or fine-tuning nucleotide production, could tip the balance toward recovery. However, this pathway's duality as a defender against ROS while also having the potential to contribute to metabolic exhaustion demands precision. As we unravel the PPP's choreography in the ischemic brain, we confront a fundamental truth: survival following stroke depends not on the function of any single pathway, but on the coordinated and dynamic interplay of metabolic networks that adapt, protect, and facilitate recovery under extreme stress.

The remarkable capacity of the peripheral nervous system (PNS) to regenerate after injury unveils a masterclass in metabolic adaptation that holds profound implications for understanding recovery in the ischemic brain. At the heart of this process lie Schwann cells, the PNS's metabolic architects, which coordinate dynamic energy reprogramming to activate regenerative programs essential for axonal regrowth [187]. Central to their strategy is MCT1, a linchpin in lactate shuttling that bridges glycolysis in Schwann cells to mitochondrial respiration in regenerating axons. Disrupting MCT1 stalls this metabolic symbiosis, delaying repair by crippling lipid metabolism and energy production, a stark reminder of lactate's dual role as both a metabolite and a signaling molecule [170]. Beyond facilitating energy exchange, Schwann cells orchestrate peripheral nerve regeneration through epigenetic reprogramming: inhibition of HDACs amplifies neuregulin signaling via PI3K-AKT/ERK pathways [103, 115], activating transcriptional programs for remyelination. Simultaneously, mTOR-1 fine-tunes protein synthesis to enable dedifferentiation into a pro-regenerative state [188]. This mTOR-driven anabolic shift, while adaptive in peripheral nerves, exhibits divergent outcomes in the central nervous system, where chronic mTORC1 activation in astrocytes drives pathological lipid synthesis and droplet accumulation via DGAT1/PLIN2 upregulation, directly linking mTOR to maladaptive glial reactivity and impaired recovery in chronic stroke phases [35, 189]. Satellite glial cells, often overshadowed by their Schwann counterparts, play a vital role similar to that of astrocytes in the central nervous system by ramping up lipid metabolism to supply axons with fatty acids for membrane rebuilding. This lipid-centric repair strategy echoes the "lipid storm" observed post-stroke, where dysregulated lipid signaling wreaks havoc; however, in the PNS, it is harnessed constructively. Beyond local metabolism, the gut-brain axis casts a surprising influence [190]. Intermittent fasting, through gut microbiota-derived metabolites like indole-3-propionate, recruits neutrophils to dorsal root ganglia, where they clear debris and prime the microenvironment for regeneration. This systemic crosstalk underscores a universal truth: nerve repair is not confined to the injury site but is a whole-body metabolic endeavor.

PNS thus offers a blueprint for metabolic resilience where glycolysis, lipid dynamics, and epigenetic plasticity converge to overcome injury. For ischemic stroke, these lessons are tantalizing. Could enhancing lactate shuttling in astrocytes, modulating HDACs to rewire glial epigenetics, or harnessing gut-derived metabolites to temper neuroinflammation similarly propel recovery in the brain? Regeneration might not be a passive process but a metabolic campaign, demanding precise resource allocation and cross-tissue coordination.

Cellular heterogeneity underpins these metabolic differences. The uniform manifold approximation and projection plot identifies nine major cell types, with excitatory neurons dominating gray matter voxels (high OXPHOS demand) and oligodendrocyte precursor cells enriched in white matter (Fig. 5b). After Z-score normalization for regional baselines (Fig. 5c), microglia exhibit discordant CI/CIV ratios indicating immunometabolic reprogramming toward pro-inflammatory M1 states via NF-κB activation, while astrocytes shift to glycolysis, exacerbating lactate accumulation and BBB compromise. Predictive neuroimaging now enables precision stratification of these vulnerabilities (Fig. 5e–g). Magnetic resonance imaging-based mitochondrial respiratory capacity (MRC) mapping reveals: BMI-driven inflammation (fluorodeoxyglucose positron emission tomography hotspots in obese patients, BMI > 30), aging signatures (MRC decline in putamen correlating with NAD⁺ depletion), and regional resilience patterns (high putamen MRC predicting lactate overproduction; low white matter MRC signaling axonal injury).

Central to therapeutic development is PGC-1α, a master regulator of mitochondrial biogenesis. Pharmacological PGC-1α agonists enhance mitochondrial genesis across neural cells, bolstering ATP production while reducing ROS through upregulated antioxidant defenses [193]. This dual action rescues energy-deprived neurons and shifts microglia from destructive M1 to reparative M2 phenotypes. Critically, these interventions require metabolic stratification: NAD⁺ precursors restore plasticity in young brains but fail in aged OXPHOS-compromised systems, while CPT1A inhibitors benefit lean subjects but worsen hepatic steatosis in obesity [194, 195].

Equally vital is preserving mitochondrial membrane integrity via mPTP inhibitors like cyclosporine A. By blocking pathological pore opening, these agents prevent the collapse of membrane potential, cytochrome c release, and caspase-driven apoptosis [196]. This sustains penumbral ATP synthesis and stabilizes astrocytic mitochondria, maintaining lactate shuttling to neurons [197]. However, prolonged mPTP blockade risks trapping damaged organelles, demanding precise dosing.

The mitochondrial-immune interplay reveals a broader truth: stroke recovery requires integrated metabolic-inflammation control. While PGC-1α agonists suppress NF-κB via NADPH synthesis [198] (Fig. 5), and mPTP inhibitors reduce mitochondrial DNA-driven TLR9-driven neutrophil infiltration [199]. However, these strategies exist within a delicate balance. Excessive mitochondrial biogenesis may exacerbate oxygen demand in hypoxic regions, and mPTP inhibition could inadvertently shield damaged mitochondria from mitophagy. Therefore, the future lies in combinatorial approaches pairing PGC-1α activation with mitophagy enhancers or coupling mPTP inhibitors with antioxidants to harmonize metabolic recovery with immune homeostasis. Mitochondrial modulation is not merely a technical fix but a reclamation of cellular equilibrium. It challenges us to view the post-stroke brain not as a battlefield of isolated pathways but as an ecosystem where energy, inflammation, and repair are inextricably linked.

In the metabolic tumult of ischemic stroke, amino acids emerge as both mediators of survival and architects of collateral damage, their fates intricately tied to the interplay between glycolytic frenzy and lipid peroxidation [100 –102, 200] (Box 2). At the epicenter lies arginine, a double-edged precursor to NO. Regulation of the arginine/NO pathway is paramount: while endothelial NO synthase (eNOS)-derived NO sustains cerebral blood flow by vasodilation, iNOS in activated glia overproduces NO, spawning neurotoxic peroxynitrite that exacerbates lipid peroxidation and mitochondrial dysfunction [201]. Therapeutic strategies aim to tip this balance by preserving eNOS activity to maintain vascular tone while silencing iNOS to curb neuroinflammation. Emerging small molecules (e.g., citric acid) selectively inhibit iNOS or bolster arginase activity, diverting arginine toward polyamine synthesis to support axonal sprouting and membrane repair, thus threading the needle between vascular protection and inflammatory mitigation [202].

Equally critical is tackling glutamate, the harbinger of excitotoxic doom. Beyond its role in neuronal hyperactivation, excess extracellular glutamate fuels oxidative stress by depleting glutathione and amplifying lipid peroxidation. Glutamate scavengers like AA147 offer a dual lifeline: by mopping up synaptic glutamate, they blunt excitotoxicity while paradoxically activating the NRF2-KEAP1 antioxidant axis [203]. This triggers a cascade of cytoprotective genes (glutamate-cysteine ligase for glutathione synthesis, heme oxygenase-1 to degrade pro-oxidant heme), effectively dousing the lipid storm's flames. Notably, NRF2 activation also reprograms macrophage metabolism, shifting them toward anti-inflammatory phenotypes that synergize with arginine pathway modulation to stabilize the neurovascular unit [204].

However, these strategies exist in metabolic crossfire. The same glycolytic surge that depletes NAD⁺, a cofactor critical for sirtuin-mediated eNOS activation, also starves the urea cycle, perturbing arginine homeostasis [205]. Similarly, lactate accumulation from anaerobic glycolysis acidifies the microenvironment, impairing NRF2 nuclear translocation and blunting AA147's efficacy. Therefore, amino acid metabolism cannot be targeted in isolation; it demands integration with interventions to normalize pH, restore redox balance, and rewire carbon flux. The promise lies in combinatorial approaches pairing arginine analogs with lactate transporter inhibitors or coupling glutamate scavengers with lipid peroxidation blockers to create a metabolic firewall against stroke's cascading insults.

In this light, amino acids are not mere metabolic substrates but dynamic signaling nodes where survival and demise converge. Their manipulation offers a path to harmonize the brain's desperate energy grabs with its fragile need for redox and ionic equilibrium, a balance as delicate as it is vital. As we chart this terrain, it is expected to transform the post-stroke milieu from a metabolic battleground (site of competing metabolic adaptations) into a scaffold where amino acids may orchestrate metabolic repair by modulating both glycolytic flux (e.g., serine-driven one-carbon metabolism) and lipid peroxidation (e.g., cysteine-dependent glutathione synthesis), though combinatorial targeting studies are needed [186, 206].

In the dysregulated substrate flux and redox imbalance during ischemic stroke (metabolic chaos), the brain's compensatory shift toward anaerobic glycolysis (a Warburg-like adaptation) initiates a pathogenic cascade: lactate accumulation drives cytotoxic acidosis while concurrently fueling enzymatic lipid peroxidation, demanding targeted strategies to modulate this maladaptive energetic response [133, 207]. HK2 and LDHA, gatekeepers of glycolytic flux, emerge as high-value targets. Inhibiting HK2 curtails the first committed step of glycolysis, reducing glucose-6-phosphate accumulation and its diversion into the PPP, while LDHA blockade prevents pyruvate-to-lactate conversion, averting extracellular acidosis and mitochondrial fragmentation. Preclinically, these inhibitors reduce infarct volumes and improve functional recovery, not merely by lowering lactate but by reprogramming cellular metabolism: forcing neurons to resurrect oxidative phosphorylation in salvageable penumbral regions and redirecting glucose toward the PPP to bolster NADPH-dependent antioxidant defenses [208, 209].

However, glycolysis inhibition is a metabolic tightrope. While curtailing lactate mitigates lipid peroxidation, sparing membranes from 4-HNE assault, it risks starving cells of ATP in regions where mitochondria are irreparably damaged [210]. This paradox underscores the need for spatiotemporal precision: delivering inhibitors post-reperfusion to avoid compromising acute survival mechanisms while promoting later repair. Intriguingly, LDHA inhibition also disrupts the lactate shuttle, silencing lactate's role as a signaling molecule that sustains pro-inflammatory microglial activation [211]. The result is a dual boon: reduced excitotoxicity and dampened neuroinflammation, though at the cost of impairing astrocyte-to-neuron metabolic support.

The therapeutic horizon lies in selectivity and synergy. Next-generation HK2/LDHA inhibitors with BBB penetrance and cell-specific targeting (preferential astrocyte vs. neuron action) could minimize off-target energy crises. Pairing these agents with mitochondrial protectors, such as cyclosporine A, or lipid peroxidation inhibitors (e.g., ferrostatin-1), may reconcile the competing demands of energy rescue and oxidative defense. In this metabolic recalibration, glycolysis inhibition transcends mere energy modulation; it becomes a strategic strike against the intersecting crises of glycolytic overdrive and lipid storm, offering a lifeline to neurons teetering between salvage and self-destruction.

The brain's immune and metabolic systems post-stroke engage in a destructive tango, glial cells and lymphocytes fuel inflammation through maladaptive glycolysis, while lipid peroxidation ravages membranes. Breaking this cycle demands interventions that simultaneously recalibrate immune responses and metabolic flux [212]. Astrocyte reprogramming stands at the forefront: forced expression of neurogenic transcription factors like NeuroD1 or Ngn2 converts reactive astrocytes into functional neurons, a feat that not only replenishes lost circuitry but also silences their pro-inflammatory secretome [213]. By transforming A₁ astrocytes, chronic producers of MMP-9 and ROS into neurons, this strategy dismantles the inflammatory scaffold that perpetuates BBB leakage and mitochondrial stress, indirectly stabilizing energy metabolism in surviving cells (Fig. 2c).

Parallel efforts target T-cell glycometabolism, where the receptor for RAGE emerges as a linchpin. RAGE signaling in Th17 cells drives a glycolytic surge, propelling their pathogenic differentiation and infiltration into the ischemic brain. Inhibiting RAGE redirects glucose away from glycolysis, suppressing IL-17A production and curtailing neutrophil recruitment, a double victory that dampens neuroinflammation while sparing glucose for reparative processes like axonal ATP synthesis [214]. This metabolic-immune shift mirrors the effects of mitochondrial modulators, as reduced Th17 activity diminishes ROS spillover, easing the burden on neuronal antioxidant systems and preserving mitochondrial membrane integrity.

However, these interventions walk a metabolic tightrope. Astrocyte-to-neuron conversion risks depleting the glial workforce essential for lactate shuttling and glutamate clearance, potentially exacerbating energy crises in penumbral regions. Similarly, RAGE inhibition may inadvertently impair beneficial Treg subsets reliant on glycolytic intermediates for anti-inflammatory function [215]. Therefore, precision is paramount: temporal targeting of NeuroD1/Neurogenin2 (Ngn2) post-acute phase, or RAGE blockade coupled with lactate supplementation, could reconcile immune modulation with metabolic support. The promise lies in their synergy; reprogrammed astrocytes may secrete neurotrophic factors that enhance mitochondrial biogenesis in newborn neurons, while subdued Th17 inflammation reduces lipid peroxidation, creating a milieu where glycolysis and oxidative phosphorylation coexist rather than clash. Immunometabolic interventions, therefore, transcend conventional immunosuppression. They represent a paradigm where immune cells and glia are not merely silenced but metabolically reprogrammed to ally with recovery, a vision where the brain's post-stroke "lipid storm" is quelled not by brute force but by strategic rewiring, transforming inflammatory arsonists into architects of renewal.

In the acute phase of ischemic stroke, where unchecked glycolysis fuels lipid peroxidation and mitochondrial dysfunction, nanoparticle-based delivery systems offer a strategy for spatially targeted intervention. These systems deliver immunometabolic modulators such as succinate directly to lesion-specific cell types, enabling localized metabolic reprogramming. Nanocarriers engineered to cross the compromised BBB represent a shift from generalized anti-inflammatory therapies to precision targeting of hyperactive microglia and neurons [216]. Succinate, a TCA cycle intermediate that accumulates during ischemia, becomes therapeutically valuable when encapsulated [217]. Delivered via pH-sensitive nanoparticles, it is selectively released in the acidic penumbra, where it competitively inhibits mitochondrial SDH, thereby blocking reverse electron transport and reducing ROS, a key trigger of NLRP3 inflammasome activation and lipid peroxidation [218]. Similarly, the immunometabolite itaconate plays a dual role in modulating neuroinflammation. Nanoparticles conjugated with microglia-targeting peptides transport itaconate to phagocytic cells, where it exerts anti-inflammatory effects by upregulating NRF2-mediated antioxidant responses and alkylating KEAP1 to stabilize HIF-1α [219]. This paradoxical action simultaneously promotes glycolytic adaptation and suppresses inflammatory signaling, highlighting nanotherapy's potential to integrate metabolic and immune modulation.

These nanocarriers are often engineered to respond to stroke-specific environmental cues such as local acidosis, oxidative stress, or vascular leakage, to achieve site-specific payload release, thus avoiding systemic side effects like succinate-induced peripheral inflammation or compromised antibacterial defense from systemic itaconate [220]. However, translation to the clinic faces biological constraints. Human microglia express roughly 50% fewer nanoparticle-targeting receptors, such as triggering receptors expressed on Myeloid cells 2 (TREM2), than rodent models, reducing cellular uptake [221]. Moreover, metabolites like itaconate degrade more rapidly in human CSF, with a half-life of 1.2 h compared to 4 h in mice [222].

Despite these challenges, new designs are showing promise. ROS-sensitive nanocarriers can release itaconate specifically in oxidatively stressed tissues [197], while lipid-coated nanoparticles can hijack immune cells to enter ischemic regions [221]. Key areas for optimization include minimizing hepatic clearance and shielding payloads from enzymatic degradation [223]. A dual-delivery strategy is emerging, such as combining succinate with SDH inhibitors or pairing itaconate with lactate transport activators to simultaneously dampen inflammasome activation and restore mitochondrial metabolism [224]. To mitigate translational risk, phase 0 microdosing studies using ⁸⁹Zr-labeled nanoparticles are proposed to assess human biodistribution prior to efficacy trials [225].

Systemic FAO inhibition with agents like etomoxir can lead to lipid redistribution and hepatic steatosis, as observed in 68% of participants in non-stroke clinical trials (NCT02904226) [226, 227]. Preclinical approaches to reduce hepatotoxicity include nanoparticle encapsulation with hepatocyte-avoidant peptides, which reduce liver uptake by up to 90%, or co-administration with PPARα agonists to enhance lipid clearance [228]. Microbiome-based therapies such as fecal microbiota transplantation (FMT) face regulatory and biological hurdles in stroke populations. The FDA mandates an Investigational New Drug (IND) application for FMT in stroke indications, requiring strain-specific GMP production with an estimated cost of $2.3 million, exclusion of immunocompromised individuals (who represent about 25% of the elderly stroke population), and rigorous monitoring for horizontal gene transfer and potential antibiotic resistance [229]. As safer alternatives, Phase I trials (NCT04756561) are evaluating lyophilized Akkermansia capsules [230, 231]. A persistent technical tradeoff in nanoparticle therapy is the balance between systemic clearance and brain penetration. Particles larger than 20 nm evade hepatic filtration but show brain uptake of less than 1%. Conversely, downsizing to <10 nm improves brain entry but raises toxicity risks, including hippocampal apoptosis in rodent models [232].

Comorbidity-specific stratification is crucial in tailoring therapeutic protocols. LDHA inhibitors pose risks in diabetic patients with unstable pH and should be avoided if lactate exceeds 5 mM, with continuous pH monitoring recommended. DGAT1 inhibitors [111], which influence lipid metabolism, are contraindicated in obese patients with FFA levels above 600 μM [233 –235], necessitating FFA screening before initiation. For succinate-loaded nanoparticles, renal impairment should be considered: dosing should be adjusted based on glomerular filtration rate (GFR), and administration avoided if the estimated GFR is below 30 mL/min [236].

CPT1A, the rate-limiting enzyme in mitochondrial FAO, is a pivotal therapeutic target in ischemic stroke due to its role in amplifying neuroinflammation. During ischemia, neurons and glia undergo metabolic reprogramming toward FAO to compensate for glycolytic collapse, generating ROS and pro-inflammatory lipid mediators (e.g., arachidonic acid derivatives) that exacerbate neurovascular injury [253]. While CPT1A inhibitors (etomoxir, perhexiline) show preclinical efficacy in reducing infarct volumes and improving motor recovery in rodents by attenuating NLRP3 inflammasome activation and IL-1β release [212], translation to humans faces significant hurdles. Crucially, human hepatocytes exhibit 10-fold higher CPT1A sensitivity than rodent models, explaining dose-limiting hepatotoxicity (ALT elevation in 60% of non-stroke trials) [129]. This species difference necessitates innovative delivery approaches like nanoparticle encapsulation to avoid hepatic exposure and patient stratification using FAO biomarkers. Plasma C16-carnitine >2 μM emerges as a promising stratification biomarker, correlating strongly with neuroinflammation severity [49]. Early clinical trials should further address comorbidity-driven metabolic rewiring, particularly in diabetes, where altered lipid metabolism amplifies neuroinflammatory cascades [254].

ACMSD, a pivotal regulator of the kynurenine pathway, offers a novel therapeutic strategy to combat NAD⁺ depletion, a core metabolic defect in stroke driving mitochondrial dysfunction and cognitive decline. Pharmacological inhibition of ACMSD amplifies NAD⁺ synthesis, restoring redox balance and enhancing sirtuin-1-mediated synaptic plasticity essential for post-stroke memory consolidation and emotional regulation [110]. While ACMSD knockdown improves cognitive recovery in aged mice [255], therapeutic translation requires careful calibration: excessive pathway activation risks accumulating neurotoxic quinolinic acid, potentially exacerbating anxiety symptoms [256 –263] (Table S6). Critically, no ACMSD-specific drugs have entered clinical trials to date. Current NAD⁺ precursors (e.g., nicotinamide riboside) show limited clinical efficacy in stroke recovery (Phase II: National Institutes of Health Stroke Scale, NIHSS of −1.2 at 90 days) [106], primarily due to poor central nervous system (CNS) bioavailability. To overcome this barrier, next-generation delivery strategies like exosome-encapsulated NAD⁺ or intranasal administration are being explored to enhance brain penetration. These advances raise important ethical considerations: as biomarker-guided metabolic therapies emerge, we should ensure equitable access for elderly populations to prevent widening recovery disparities.

TRF, which aligns caloric intake with circadian-active phases, exemplifies how metabolic reprogramming intersects with human behavior to shape stroke recovery. By synchronizing peripheral and central circadian rhythms, TRF restores the body's natural metabolic oscillations, optimizing glucose utilization during active hours and ketogenesis during rest, a process critical for mitigating post-stroke neuroinflammation and mitochondrial dysfunction [264]. In rodent models, TRF not only reduces infarct size but also enhances motor recovery, suggesting that metabolic timing influences neural repair mechanisms [265]. Human pilot trials reveal that TRF improves insulin sensitivity and dampens systemic inflammation [266], yet its success hinges on behavioral adherence, as societal norms around irregular eating schedules and shift work often clash with circadian-aligned feeding. Personalized TRF regimens, adapted to individual chronotypes (e.g., "night owls" vs. "early birds"), could harmonize metabolic benefits with lifestyle preferences, thereby enhancing rehabilitation participation and reducing post-stroke fatigue. However, socioeconomic disparities in meal timing flexibility, such as limited control over work hours or access to nutritious food, risk excluding vulnerable populations from TRF's advantages. Integrating TRF into stroke care thus demands more than biological insight; it requires addressing the cultural, economic, and psychological barriers that dictate daily eating patterns. When viewed through the MRIS lens, TRF becomes a behavioral-metabolic intervention, where the simple act of when we eat transforms cellular survival strategies into tangible improvements in cognitive function, emotional resilience, and community reintegration.

The gut-brain axis emerges as a critical mediator of post-stroke neurobehavioral recovery, with Akkermansia muciniphila, a keystone gut bacterium, serving as both a metabolic architect and a behavioral modulator [267]. Post-stroke dysbiosis depletes Akkermansia, exacerbating BBB leakage and microglial activation. Fecal microbiota transplantation from Akkermansia-rich donors in mice restores butyrate levels, upregulates cerebral claudin-5 expression, and polarizes microglia toward an anti-inflammatory M2 phenotype [268]. By enhancing SCFA production, Akkermansia fortifies gut barrier integrity, reducing endotoxin-driven neuroinflammation and BBB leakage, processes that directly influence cognitive dysfunction and emotional dysregulation in stroke survivors [269]. Clinical trials reveal that Akkermansia supplementation elevates circulating butyrate levels, correlating not only with improved neurological scores but also with enhanced patient motivation and engagement in rehabilitation, likely via butyrate's role in dopaminergic signaling [269]. However, this therapeutic promise is tempered by societal and practical challenges: socioeconomic disparities in dietary fiber access limit endogenous Akkermansia abundance in marginalized populations. Synbiotic strategies pairing Akkermansia with culturally adaptable prebiotics (inulin-rich local staples) may democratize access, ensuring microbiome interventions align with diverse dietary practices. Therefore, fecal microbiota transplantation represents a metabolic-behavioral intervention, where restoring gut ecology can recalibrate the brain's inflammatory tone, turning the gut into an ally in the battle against post-stroke apathy and social withdrawal.

Multidimensional metabolic phenotyping represents a transformative approach, integrating spatial lipidomics to map arachidonic acid cascades [49], CSF panels quantifying lactate, itaconate, and NAD⁺ ratios [106, 273], and machine learning algorithms that synthesize plasma biomarkers with neuroimaging and genomic data [49]. This enables precision interventions: DGAT1 inhibitors for APOE ε4 carriers with astrocytic lipid droplets [90, 98, 99, 270], or NAD⁺ salvage for aged SIRT1-deficient penumbras with NAMPT variants [244, 245]. Concurrently, safety-aware designs should address hepatic monitoring for FAO inhibitors (etomoxir elevates liver triglycerides by 40%) [274]; cancer risk stratification for NAD⁺ boosters in SLC2A1 variant carriers [275]; and immunosuppression screening for fecal transplants [276].

A comprehensive approach to MRIS therapy integrates biomarker-driven patient stratification, circadian-informed treatment timing, and the engineering of peripheral-central metabolic crosstalk to enhance stroke recovery. Precise identification of metabolic subphenotypes enables the selection of interventions that match individual pathophysiology, while chronotherapeutic strategies align treatment delivery with endogenous metabolic rhythms to maximize efficacy and minimize side effects (Table). By combining these approaches with modulation of peripheral organ systems, this framework can transform stroke management from isolated vascular treatment to a coordinated, systemic metabolic rehabilitation. S7