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SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review)

  • Authors:
    • Irum Naz Abbasi
    • Nashwa Amin
    • Qiaolu Xu
    • Azhar Badry Hussain
    • Fei Wu
    • Xia Yuan
    • Yang Yang
    • Suhong Ye
    • Marong Fang
    • Yihua Jiang
  • View Affiliations / Copyright

    Affiliations: Department of Orthopedics, National Clinical Research Center for Children and Adolescents' Health and Diseases, Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310052, P.R. China, Institute of System Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China, Psychiatry Department, The Second Hospital of Jinhua, Jinhua, Zhejiang 321004, P.R. China, Faculty of Medicine, Macau University of Science and Technology, Macau SAR 999078, P.R. China, Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China
    Copyright: © Abbasi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 215
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    Published online on: June 2, 2026
       https://doi.org/10.3892/mmr.2026.13926
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Abstract

The increased prevalence of stroke around the globe is a notable challenge as there are few treatments and the long‑term effects include neurological impairment. Oxidative stress, mitochondrial dysfunction and neuroinflammation are key mechanisms underlying the complex pathophysiology of stroke, yet their precise interactions remain poorly understood. Notably, the silent information regulator 2 homolog 1 (SIRT1)/AMP‑activated protein kinase (AMPK)/peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC1α) pathway contributes to the neuronal protection against stroke damage. The possible beneficial effects through modulations of this pathway are explored in the present review, in particular, how flavonoids may provide a promising solution to reducing the consequences of stroke. Over the years, there has been a focus on treatments using alternative methods, leaving behind the traditional drugs‑based approaches. These involve researching the impacts of physical activity and caloric intake and assessing the possible advantages of naturally available products. This versatile approach provides new prospects of therapeutic development. The present comprehensive review aimed to understand the complexity of SIRT1/AMPK/PGC1α pathway with the aim to identify potential multi‑target therapeutic approaches to reduce the notable effects of stroke on global health and wellbeing and offer new promise in the current management of ischemic stroke. The present review demonstrates that SIRT1/AMPK/PGC1α is a key neuroprotective target in stroke. Moreover, it reveals that flavonoids combined with exercise and caloric restriction enhance treatment, and that flavonoid nanoparticles crossing the blood‑brain barrier offer neuroprotection. Finally, the review focuses on brain PGC1α, improved delivery and trials performed to advance stroke therapy.
View Figures

Figure 1

The SIRT1/AMPK/PGC1α pathway protects
the brain from ischemic stroke damage. Stroke inhibits the
neuroprotective function of this cell signaling pathway, causing
oxidative stress, mitochondrial dysfunction and inflammation.
Therapeutic strategies, such as flavonoids, calorie restriction and
physical activity, could activate this pathway, promoting
mitochondrial biogenesis leading to neuroprotection. SIRT1, silent
information regulator 2 homolog 1; AMPK, AMP-activated protein
kinase; PGC1α, peroxisome proliferator-activated receptor γ
coactivator 1-α.

Figure 2

The SIRT1-AMPK-PGC1α signaling
pathway serves an essential function in both physiological and
diseased states. In healthy states, SIRT1 and AMPK react in
response to reduced energy availability or diminished metabolic
breakdown rates, initiating the addition of phosphate groups and
removal acetyl groups from PGC1α, in that order. However, during a
stroke, reduced activation of AMPK and SIRT1 prevents PGC1α from
undergoing deacetylation and phosphorylation, hindering its
translocation to the nucleus. This distortion has been reported to
impact several vital processes, such as the management of ROS
levels, the regulation of Mitochondrial Homeostasis, the
encouragement of Autophagy, control over Neuroinflammation and
assistance in Synapse formation that consequently led to stroke.
Based on the theory by Rakshe et al (24). SIRT1, silent information regulator
2 homolog 1; AMPK, AMP-activated protein kinase; ROS, reactive
oxygen species; PGC1α, peroxisome proliferator-activated receptor γ
coactivator 1-α.

Figure 3

In stroke, PGC1α has neuroprotective
properties by modulating multiple signaling cascades that
participate in the progression of the disease. These pathways
include impaired mitochondrial function, oxidative stress,
proteasome impairment, neuroinflammatory responses along with
autophagic and apoptotic processes. By targeting these pathogenic
processes, PGC1α greatly participates in the preservation of
neuronal cells in stroke (108).
Activation of PGC1α inhibits microglial activation by decreasing
cytokine generation and cell death through inhibition of Bax and
IL-1β and augmentation of Bcl-2. PGC1α enhances antioxidant,
mitochondria biogenesis, O2 consumption membrane
potential cellular recycling and the function of transcription
factors. Consequently, PGC1α activators show promise in controlling
gene expression supporting neuronal survival and offering
protective effects in neurons by addressing mitochondrial
malfunction oxidative damage proteasome impairment, autophagic
processes, neuroinflammatory responses and cell death (109). PGC1α, peroxisome
proliferator-activated receptor γ coactivator 1-α; ROS, reactive
oxygen species; AMPK, AMP-activated protein kinase.
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Copy and paste a formatted citation
Spandidos Publications style
Abbasi IN, Amin N, Xu Q, Hussain AB, Wu F, Yuan X, Yang Y, Ye S, Fang M, Jiang Y, Jiang Y, et al: SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review). Mol Med Rep 34: 215, 2026.
APA
Abbasi, I.N., Amin, N., Xu, Q., Hussain, A.B., Wu, F., Yuan, X. ... Jiang, Y. (2026). SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review). Molecular Medicine Reports, 34, 215. https://doi.org/10.3892/mmr.2026.13926
MLA
Abbasi, I. N., Amin, N., Xu, Q., Hussain, A. B., Wu, F., Yuan, X., Yang, Y., Ye, S., Fang, M., Jiang, Y."SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review)". Molecular Medicine Reports 34.2 (2026): 215.
Chicago
Abbasi, I. N., Amin, N., Xu, Q., Hussain, A. B., Wu, F., Yuan, X., Yang, Y., Ye, S., Fang, M., Jiang, Y."SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review)". Molecular Medicine Reports 34, no. 2 (2026): 215. https://doi.org/10.3892/mmr.2026.13926
Copy and paste a formatted citation
x
Spandidos Publications style
Abbasi IN, Amin N, Xu Q, Hussain AB, Wu F, Yuan X, Yang Y, Ye S, Fang M, Jiang Y, Jiang Y, et al: SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review). Mol Med Rep 34: 215, 2026.
APA
Abbasi, I.N., Amin, N., Xu, Q., Hussain, A.B., Wu, F., Yuan, X. ... Jiang, Y. (2026). SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review). Molecular Medicine Reports, 34, 215. https://doi.org/10.3892/mmr.2026.13926
MLA
Abbasi, I. N., Amin, N., Xu, Q., Hussain, A. B., Wu, F., Yuan, X., Yang, Y., Ye, S., Fang, M., Jiang, Y."SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review)". Molecular Medicine Reports 34.2 (2026): 215.
Chicago
Abbasi, I. N., Amin, N., Xu, Q., Hussain, A. B., Wu, F., Yuan, X., Yang, Y., Ye, S., Fang, M., Jiang, Y."SIRT1/AMPK/PGC1α pathway in ischemic stroke: Elucidating neuroprotective strategies (Review)". Molecular Medicine Reports 34, no. 2 (2026): 215. https://doi.org/10.3892/mmr.2026.13926
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