Globally, stroke is the second largest cause of death, and ischemic strokes make up >60% of all strokes (1). Moreover, it is a main cause of neurological problems and long-term disability in resource-poor settings (1,2). Ischemia occurs when cerebral blood flow to the brain is suddenly reduced or blocked, triggering oxidative stress, damaged mitochondria and inflammation (3,4). These events collectively lead to nerve cell injury and degeneration causing sustained neurological deficits (5).

The silent information regulator 2 homolog (SIRT) 1/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) pathway has been recognized as a key controller of cell metabolism, new mitochondria formation and neuroprotection (6,7). Activation of this pathway reduces oxidative stress, enhances mitochondrial function and decreases neuronal damage, highlighting its therapeutic potential in the treatment of ischemic stroke (8,9). However, whilst individual aspects of this pathway have been assessed in numerous neurological conditions, a systemic review providing an integrated view specifically for ischemic stroke is lacking (10,11).

We hypothesize that the SIRT1/AMPK/PGC1α pathway mediates endogenous neuroprotection in ischemic stroke, and that its targeted regulation offers promise for therapeutic development. The present review had three primary aims: i) To synthesize and evaluate research on the role of this pathway in stroke pathology and recovery; ii) to integrate findings on multi-targeted therapeutic approaches (such as flavonoids, physical activity and caloric restriction) that confer protection via this pathway; and iii) to highlight emerging research directions, including brain-specific PGC1α isoforms and novel drug carrier systems that pass through the blood-brain barrier (BBB). Overall, the present review aimed to elucidate the complex function of this pathway and establish a foundation for innovative treatment strategies for ischemic stroke. A conceptual model summarizing these aims is presented in Fig. 1.

Sirtuins, particularly SIRT1, confer neuroprotective effects during ischemic events by mitigating stroke-induced damage (12,13). These proteins function to deacetylate histones and transcription factors, thereby regulating gene expression and the activity of metabolic enzymes in response to ischemic stress. Mammals have seven types of sirtuins (SIRT1-SIRT7), with SIRT1 being the most extensively investigated when it comes to ischemia (14). When SIRT1 is activated or upregulated, it mitigates ischemic brain injury, reduces infarct size and enhances neurological outcomes (15,16). SIRT1 deacetylates transcription factors and coactivators, including PGC1α, thereby enhancing the activation of genes that are crucial for brain recovery following ischemic injury (17).

Moreover, lower AMPK activity within the brain and spinal cord [central nervous system (CNS)] is also associated with increased pathology in conditions such as Alzheimer's disease (18,19). By contrast, when AMPK is activated, it raises NAD+ levels and thereby activates SIRT1. As a result, this promotes neuroprotection (20–22).

The co-activator PGC1α also has a notable role in the production of new mitochondria and the scavenging of reactive oxygen species (ROS) (23,24). Its expression is mainly restricted to tissues with high energy demands (such as the brain) and is regulated by metabolic stimuli such as caloric restriction, physical exercise or hypoxia (25). Notably, PGC1α is markedly expressed in certain areas of the brain (cortex and striatum), whereas it is not found in the hypothalamus (26). Structural models suggest that PGC1α promotes polymerase II recruitment with the cooperation of transcription factors of the nuclear receptor family, such as peroxisome proliferator activated receptors (PPARs), estrogen receptor α and retinoid × receptor α (25,27). This mechanism is mediated through acetyl and methyltransferase protein groups along with helper proteins such as steroid receptor coactivator 1, CRE-binding proteins (CBP/p300) (28). The distribution of PGC1α between the nucleus and cytoplasm is modulated by energy-sensing molecules, including SIRT1, AMPK and histone acetyltransferases (29). The acetylation of PGC1α, which is directly mediated by the general control non-repressed 5 protein, leads to a reduction in how well it can activate gene transcription (23). Under conditions of energy stress, the NAD+/NADH ratio is elevated, leading to the activation of SIRT1. Subsequently, SIRT1 deacetylates PGC1α, thereby enhancing its transcriptional activity and then increasing the generation of antioxidant proteins, including glutathione peroxidase and superoxide dismutase (24,30). AMPK additionally activates the PGC1α/SIRT1-dependent antioxidant system by enhancing the expression of antioxidant enzymes, thereby sustaining mitochondrial equilibrium during disruptions in cellular energy (29,31).

The interaction among SIRT1, AMPK and PGC1α is of notable importance, establishing a pathway with therapeutic potential for diseases associated with aging, particularly those impacting the nervous system (Table I) (32). Specifically, excessive activation of AMPK may adversely affect synaptic plasticity by inhibiting MORC1 (31) and sustained overexpression of SIRT1 could enhance metabolic resilience in cancer cells (33). Additionally, an increase in PGC1α has been associated with elevated oxidative stress in neurons affected by Parkinson's disease (33). Furthermore, inflammatory signals and metabolic stress may attenuate the benefit of this pathway (34).

The present review distinctively emphasizes the collaborative mechanisms by which these proteins regulate mitochondrial function, oxidative stress and neuroinflammation, thereby providing novel insights into multi-targeted treatment approaches. Additionally, future studies should evaluate the role of CNS-specific PGC1α isoforms, which may represent new therapeutic targets for stroke recovery.

The SIRT1/AMPK/PGC1α pathway is a notable protective survival signal in neurons as it controls cellular metabolism, energy homeostasis and neuroprotection. The upregulation of this pathway provides a potential therapeutic target for ischemic stroke (55). AMPK, an energy sensor, serves as a primary controller of bioenergetic metabolism and cellular growth. Its activation by phosphorylation of the α subunit at Thr172 is anti-apoptotic and anti-neuroinflammatory leading to increased cell survival (49). AMPK activates SIRT1 by increasing cellular NAD+ levels, which acts as an essential co-substrate for SIRT1 deacetylation of LKB1. This reciprocal crosstalk modulates the PGC1α, FOXO1 and NF-κB signaling axis, leading to reduced apoptosis and inflammation and enhanced neuronal survival (25). The decreased PGC1α is associated with elevated oxidative stress levels, reduced mitochondrial number and neuronal loss. On the other hand, the SIRT1/AMPK/PGC1α axis is beneficial for the neuronal survival and mitochondrial function during ischemic stroke (6). For example, the adipokine CTRP3 activates this pathway, protects mitochondrial function and controls mitochondrial dynamics such as fission and fusion. Within hippocampal neurons subjected to oxygen-glucose deprivation followed by reperfusion, CTRP3 enhanced viability, reduced apoptosis and promoted mitochondrial biogenesis whereas PGC1α silencing abolished these protective effects (7).

Previous research has underscored the neuroprotective function of PGC1α. Mice deficient in PGC1α were reported to have increased infarct sizes, notable motor and cognitive impairments and elevated oxidative stress and inflammation following a stroke (9,10). These observations highlight the neuroprotective function of PGC1α within the context of cerebral ischemia and suggest the possibility of using it as a therapeutic candidate for managing stroke.

The SIRT1/AMPK/PGC1α pathway is integral to neuroprotection following ischemic stroke, as it modulates inflammation, oxidative stress and mitochondrial function (56). Notably, in vivo studies provide data supporting their therapeutic utility. The knockout or inhibition of SIRT1 (such as using EX527) negates (i.e., abolishes) the neuroprotective effects of compounds such as resveratrol and enhances HMGB1 acetylation and NLRP3 inflammasome activation, thereby confirming that loss of SIRT1 activity is detrimental and exacerbates ischemic injury (57). In mice subjected to 1-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 24 h, resveratrol was associated with reduced infarct size, brain edema and neurological impairments via SIRT1 dependent autophagy, as these effects were blocked by 3-methyladenine or SIRT1 small interfering RNA. In permanent focal ischemia, SIRT1 activation (activator 3, 10 mg/kg) was associated with reduced infarct volume, whereas SIRT1 inhibition (sirtinol, 10 mg/kg) and SIRT1 deletion were associated with enlarged injury and increased p53/NF-kB acetylation (6).

Similarly, AMPKα-deficient mice or those treated with AMPK inhibitors (such as compound C) exhibit increased infarct volume, enhanced neuronal death and worsened neurological deficits, underscoring the essential role of AMPK in mitochondrial biogenesis and neuronal survival (24). Furthermore, PGC1α knockout or knockdown were associated with compromised mitochondrial function and heightened neuronal susceptibility, emphasizing its neuroprotective function (58). In a rodent photothrombotic stroke model, intranasal mitochondrial administration (100 µg protein), given at 30 min, 24 and 48 h, was associated with reduced infarct volume and edema with increased p-AMPKα, PGC1α and restored SIRT1 (59).

Collectively, these findings substantiate the involvement of SIRT1, AMPKα and PGC1α in stroke protection, rendering them promising therapeutic targets. Despite the overall neuroprotective role of this axis, the strength of evidence varies across its components. SIRT1 activation consistently reduces infarct volume and inflammation, whereas AMPKα exhibits context-dependent effects; early post stroke activation reduces neuronal death and promotes autophagy, while excessive or late activation may exacerbate apoptosis under energy depleted conditions (60). Similarly, autophagy regulation via this axis shows duality, with both pro-autophagic and anti-autophagic strategies reported as protective. By contrast, the SIRT1/PGC1α arm demonstrate more consistent benefits in mitochondrial preservation. Taken together, these observations suggest that while the pathway is a promising therapeutic target, its actions are notably context-sensitive and require careful consideration of timing, magnitude and cell type specificity (61). Furthermore, the administration of quercetin has been reported to mitigate oxidative stress and promote neuronal recovery by upregulating phosphorylated AMPK, PGC1α, SIRT1, NRF1 and Tfam (53,62). Furthermore, Icariin has been reported to facilitate mitochondrial biogenesis and mitigates ROS through the activation of AMPK, highlighting the notable role of mitochondrial regulation in the recovery process following a stroke (63,64). SIRT1 has also been reported to attenuate neuroinflammation through inhibition of NF-κB and lowering oxidative stress. The elevated levels of SIRT1 observed in human patients with stroke indicate its potential as a biomarker for assessing stroke severity (65–67). These findings collectively underscore how critical the SIRT1/AMPK/PGC1α axis in ischemic stroke, elucidating its connection to metabolic disturbances, neuroinflammation and mitochondrial dysfunction. Therefore, modulating this axis offers a promising strategy for mitigating neuronal damage and enhancing recovery (Fig. 3).

Despite encouraging preclinical results, key knowledge gaps remain before the SIRT1/AMPK/PGC1α axis can be translated into stroke therapy. Most studies use young rodent models with short observation windows, whereas clinical stroke occurs in older patients with comorbidities (such as hypertension and diabetes) (102). Pathway effects are cell and phase specific; AMPK and autophagy can be protective or detrimental depending on context. Direct evidence linking pathway activation to sustained functional recovery remains limited, and human evidence is sparse. Serum SIRT1 levels in patients with stroke show no association with clinical outcomes, highlighting the gap between experimental promise and clinical utility (61). Recent advances have identified novel brain specific isoforms of PGC1α in human neural tissue, regulated by CNS-specific promoters located ~500 kilobases upstream of the canonical promoter (24). Among these, a truncated 17 kDa isoform has garnered attention for its potential role in suppressing full length PGC1α, thereby contributing to stroke pathology (25). However, while these findings are promising, they remain at a preclinical and mechanistic stage. Further research is required to elucidate the physiological and pathological functions of these isoforms before they can be translated into therapeutic targets for ischemic stroke.

Epigenetic modulation of PGC1α via DNA methylation and nucleosome positioning also presents a compelling therapeutic concept (103). DNA methyltransferases (3A and 3B) influence these epigenetic marks, which are associated with mitochondrial dysfunction and oxidative stress (104). Although these mechanisms have been demonstrated in experimental settings, clinical application remains exploratory. Targeting epigenetic regulators could offer novel stroke therapies; however, such approaches require validation in translational models.

By contrast, modulation of the SIRT1/AMPK/PGC1α pathway through existing pharmacological agents offers more immediate translational potential. Agents such as flavonoids (quercetin) and metabolic regulators (resveratrol or metformin) (105) have demonstrated neuroprotective effects and are currently under investigation in clinical and preclinical contexts (106). Their combination with non-pharmacological strategies such as exercise and caloric restriction presents a feasible, multi model approach to enhancing mitochondrial biogenesis and neuroprotection in stroke recovery (24).

Similarly, PPARγ agonists, known to activate PGC1α, have demonstrated effectiveness in enhancing mitochondrial performance and lowering oxidative damage (107). However, their clinical utility is limited by challenges such as poor BBB penetration during stroke, adverse side effects (for example, anemia and edema) and narrow therapeutic windows. Therefore, while these agents are closer to clinical use than isoform targeting or epigenetic therapies, further optimization of BBB permeable formulations and dosing strategies is critical.

Future research should prioritize strategies with high translational potential such as enhancing PGC1α activation through well characterized pharmacological and lifestyle intervention. Parallel exploration of emerging but less clinically validated areas such as isoform-specific regulation and epigenetic targeting may open novel therapeutic avenues in the longer term. Integrating these approaches can improve stroke outcomes and broaden the therapeutic landscape for neurodegeneration.

The SIRT1/AMPK/PGC1α signaling pathway constitutes a viable therapeutic target for cerebral ischemia. Nevertheless, the intricate nature of stroke pathophysiology necessitates the development of multi-targeted treatment strategies for effective intervention. The synergism between phytochemicals and non-pharmacological interventions such as exercise and caloric restriction has shown promise in targeting the essential mechanisms in stroke such as mitochondrial dysfunction, oxidative stress and neuroinflammation (108). These approaches may also reduce age related impairments in cognition, the nervous system and memory, potentially through modulation of the SIRT1/AMPK/PGC1α pathway. Advances in the base formulations and drug delivery methods of flavonoids, including the nano formulations able to traverse the BBB, offer new hopes for neuroprotective interventions. In addition, the possible synergistic effects combining phytochemicals with an exercise modality, such as yoga, warrant further evaluation as they may offer potential benefits in terms of reduced toxicity and treatment costs, which could be explored for future prevention and intervention strategies.

In summary, the present review provides insights into the therapeutic benefits of activating the SIRT1/AMPK/PGC1α signaling axis in ischemic stroke and emphasizes that multi-targeted strategies, including pharmacological interventions and non-pharmacological interventions, are an essential factor to modulate mediators for neuroprotection. It also highlights the potential therapeutic effect of brain PGC1α isoforms, BBB-permeable delivery systems and epigenetic regulation as promising therapeutic targets (109). Through targeting several pathological mechanisms, these new development strategies provide hopeful therapeutic avenues of improving patient outcome and reducing the global burden of ischemic stroke. In order to further enhance the application of stroke therapy new adjuvant drug delivery systems capable of enhancing BBB penetration and flavonoid bioavailability need to be developed. In addition, the brain-specific PGC1α isoforms need to be addressed for therapeutic precision. It would be necessary to validate efficacy by performing clinical trials using standardized dosing regimens, formulations and patient classification.