SS-31 improves post-cardiac arrest brain injury by inhibiting microglial ferroptosis and polarization.

Jiang T, Zhang H, Sun Y, Ji X, Xue L, Pan C, Guo Y, Xu F

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics24 Oct 2025Cited by 4 (Europe PMC)

PMID41136322PMCIDPMC12976541DOI10.1016/j.neurot.2025.e00772PepBankPUB-41136322

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Summary

Accumulating evidence suggests that ferroptosis and mitochondrial dysfunction contribute significantly to brain injury following cardiac arrest (CA) and resuscitation. SS-31, a novel mitochondria-targeting peptide, has demonstrated protective effects against mitochondrial dysfunction induced by ischemia/reperfusion injury. This study aimed to investigate the neuroprotective effects of SS-31 in post-CA brain injury and clarify the underlying signaling mechanisms. An in vivo rat model of CA and resuscitation was established. Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group. Survival rates, neurological deficit scores, serum neuronal injury markers (NSE and S100B), and histopathological changes were evaluated for up to 72 h post-resuscitation. Mechanistically, ferroptosis-related signaling pathways were examined, including glutathione peroxidase 4 (GPX4) expression, iron accumulation, oxidative stress markers, and pro-inflammatory cytokine levels, utilizing microglia-specific Sesn2 knockdown via adeno-associated virus vectors. In vitro experiments were performed on BV2 cells subjected to oxygen-glucose deprivation/reoxygenation, assessing cell viability, lipid peroxidation, ferroptosis-associated protein expression, and cytokine secretion following SS-31 intervention. Brain injury post-CA and resuscitation is significantly accompanied by ferroptosis of microglia. Treatment with SS-31 substantially improved survival rates, reduced neurological deficits, and lowered serum NSE and S100B levels. Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines. These effects were primarily mediated via the Sesn2 signaling pathway. SS-31 could effectively improve post-CA brain injury, in which the mechanism was potentially related to the inhibition of microglial ferroptosis and polarization through the regulation of Sesn2 signaling pathway.

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

Results from this study11

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

01AnimalAnimal study (in vivo)Efficacy outcome
In rats after cardiac arrest and resuscitation, SS‑31 treatment improved survival rates versus saline.
In plain wordsIn rats after cardiac arrest, SS‑31 treatment improved survival compared with saline.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseSurvival rate after cardiac arrest
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Mortality · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Treatment with SS-31 substantially improved survival rates
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632201
02AnimalAnimal study (in vivo)Efficacy outcome
In rats after cardiac arrest and resuscitation, SS‑31 treatment reduced neurological deficits versus saline.
In plain wordsIn rats after cardiac arrest, SS‑31 treatment lowered brain-related deficits compared with saline.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseNeurological deficit score
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
reduced neurological deficits, and lowered serum NSE and S100B levels.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632202
03AnimalAnimal study (in vivo)Efficacy outcome
In rats after cardiac arrest and resuscitation, SS‑31 treatment lowered serum NSE versus saline.
In plain wordsIn rats after cardiac arrest, SS‑31 lowered a blood marker of nerve cell injury (NSE) compared with saline.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseSerum NSE
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
lowered serum NSE and S100B levels.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632203
04AnimalAnimal study (in vivo)Efficacy outcome
In rats after cardiac arrest and resuscitation, SS‑31 treatment lowered serum S100B versus saline.
In plain wordsIn rats after cardiac arrest, SS‑31 lowered a blood marker of brain injury (S100B) compared with saline.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseSerum S100B
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
lowered serum NSE and S100B levels.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632204
05AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 attenuated ferroptosis in microglia.
In plain wordsIn rats after cardiac arrest, SS‑31 reduced a form of cell death (ferroptosis) in brain immune cells.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseMicroglial ferroptosis
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632205
06AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 promoted an anti-inflammatory shift in microglial polarization.
In plain wordsIn rats after cardiac arrest, SS‑31 pushed brain immune cells toward an anti-inflammatory state.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseAnti-inflammatory microglial polarization
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632206
07AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 enhanced GPX4 expression.
In plain wordsIn rats after cardiac arrest, SS‑31 raised levels of GPX4, a protein that protects cells from ferroptosis.
Peptide
Elamipretide (SS-31)
Outcome
IncreaseGPX4 expression
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632207
08AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 decreased iron content.
In plain wordsIn rats after cardiac arrest, SS‑31 lowered iron content.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseIron content
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632208
09AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 decreased oxidative stress.
In plain wordsIn rats after cardiac arrest, SS‑31 lowered oxidative stress.
Peptide
Elamipretide (SS-31)
Outcome
DecreaseOxidative stress markers
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632209
10AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, SS‑31 decreased pro-inflammatory cytokines.
In plain wordsIn rats after cardiac arrest, SS‑31 lowered inflammatory signalling molecules.
Peptide
Elamipretide (SS-31)
Outcome
DecreasePro-inflammatory cytokines
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632210
11AnimalAnimal study (in vivo)Mechanism
In rats after cardiac arrest, the effects of SS‑31 were primarily mediated via the Sesn2 signaling pathway.
In plain wordsIn rats after cardiac arrest, the effects of SS‑31 depended mainly on the Sesn2 pathway.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableRole of Sesn2 signaling in SS-31 effects
Study
ratn: not reported in source
Rat model of cardiac arrest and resuscitation
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
These effects were primarily mediated via the Sesn2 signaling pathway.
2 context sentences(design, population, supporting numbers)
Summary · context
An in vivo rat model of CA and resuscitation was established.
Summary · context
Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group.
Show in the study text Report a problemFND-4113632211

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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