Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic-reperfusion injury by targeting the NOX2/AMPK pathway.

Chen Y, Guan B, Lu J, Yan X, Huang C, Qiu Y, Li X, Sun X, Chen L, Li W, Mao W, Sun Z, Xu B, Li S, Chen C

Frontiers in cell and developmental biology22 Jul 2025Cited by 9 (Europe PMC)

PMID40766780PMCIDPMC12321891DOI10.3389/fcell.2025.1623846PepBankPUB-40766780

Summary

AimThis study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia-reperfusion injury (MIRI) and the underlying mechanisms.MethodsAn MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dysfunction and myocardial infarction size were evaluated by echocardiography and triphenyltetrazolium chloride (TTC) staining. PANoptosis, ferroptosis, and mitochondrial redox state were examined by immunofluorescence, Western blotting, and an ELISA kit. In addition, molecular and biochemical methods were applied to illustrate the exact mechanisms of GI on MIRI.ResultsGI pretreatment alleviated cellular oxidative stress, inhibited PANoptosis and ferroptosis, reduced myocardial infarction area, and improved cardiac function during MIRI. Further results revealed that mitochondrial biogenesis and the anti-oxidative system were impaired in mice suffering from MIRI, and these effects were significantly alleviated by GI treatment via downregulation of the NADPH oxidase 2 (NOX2) level. Moreover, NOX2 promoted mitochondrial dysfunction by suppressing the AMP-activated protein kinase (AMPK)-PGC-1α-Sirt3 signaling pathway. In addition, the NOX2 activator exacerbated oxidative damage and offset all the beneficial effects of GI on mitochondrial function, PANoptosis, and ferroptosis. Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.ConclusionGI pretreatment protected the cardiomyocytes from MIRI-induced PANoptosis and ferroptosis by maintaining the mitochondrial redox state and biogenesis through the modulation of the NOX2/AMPK signaling pathway. Our findings indicate that GI pretreatment could be a promising therapeutic agent for MIRI treatment.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Mechanism
In the myocardial ischemia-reperfusion injury study, AICAR reinforced AMPK phosphorylation.
In plain wordsIn the mouse heart-injury study, AICAR increased AMPK phosphorylation.
Peptide
AICAR (acadesine)
Outcome
IncreaseAMPK phosphorylation
Study
mousen: not reported in source
Myocardial ischemia-reperfusion injury
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
Show in the study text Report a problemFND-4076678001
02AnimalAnimal study (in vivo)Mechanism
In the myocardial ischemia-reperfusion injury study, AICAR-associated AMPK phosphorylation maintained mitochondrial redox state.
In plain wordsIn the mouse heart-injury study, AICAR-associated AMPK activation maintained mitochondrial redox state.
Peptide
AICAR (acadesine)
Outcome
Direction not reportedMitochondrial redox state
Study
mousen: not reported in source
Myocardial ischemia-reperfusion injury
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
Show in the study text Report a problemFND-4076678002
03AnimalAnimal study (in vivo)Mechanism
In the myocardial ischemia-reperfusion injury study, AICAR-associated AMPK phosphorylation maintained mitochondrial biogenesis.
In plain wordsIn the mouse heart-injury study, AICAR-associated AMPK activation maintained mitochondrial production.
Peptide
AICAR (acadesine)
Outcome
Direction not reportedMitochondrial biogenesis
Study
mousen: not reported in source
Myocardial ischemia-reperfusion injury
Outcome group
Mitochondrial function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
Show in the study text Report a problemFND-4076678003
04AnimalAnimal study (in vivo)Mechanism
In the myocardial ischemia-reperfusion injury study, AICAR-associated AMPK phosphorylation suppressed PANoptosis.
In plain wordsIn the mouse heart-injury study, AICAR-associated AMPK activation suppressed PANoptosis cell death.
Peptide
AICAR (acadesine)
Outcome
DecreasePANoptosis
Study
mousen: not reported in source
Myocardial ischemia-reperfusion injury
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
Show in the study text Report a problemFND-4076678004
05AnimalAnimal study (in vivo)Mechanism
In the myocardial ischemia-reperfusion injury study, AICAR-associated AMPK phosphorylation suppressed ferroptosis.
In plain wordsIn the mouse heart-injury study, AICAR-associated AMPK activation suppressed ferroptosis cell death.
Peptide
AICAR (acadesine)
Outcome
DecreaseFerroptosis
Study
mousen: not reported in source
Myocardial ischemia-reperfusion injury
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.
Show in the study text Report a problemFND-4076678005

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Version history

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Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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