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Background <p>The brain energy crisis following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is a major contributor to poor neurological outcomes. While lactate is traditionally viewed as a metabolic byproduct, its potential as an alternative metabolic substrate and as a signaling molecule remains controversial. This study investigates whether exogenous lactate administration (ELA) mitigates post-cardiac arrest brain injury (PCABI) and explores the underlying mechanisms.</p> Methods <p>A rat model of CA/CPR and HT22 neurons subjected to oxygen-glucose deprivation/reoxygenation were employed. Multi-omics profiling, metabolic flux analysis, immunofluorescence, transmission electron microscopy, co-immunoprecipitation, and gene knockdown, were employed to dissect the underlying mechanisms.</p> Results <p>ELA significantly improved 5-day survival, neurological function, and neuronal integrity in CA/CPR rats. Metabolomic and proteomic analyses revealed that ELA reprogrammed energy metabolism by alleviating the post-ischemic glycolytic surge, enhancing electron transport chain activity, and restoring the ATP/ADP ratio. In vitro, ELA’s neuroprotection was dependent on its cellular uptake and metabolic utilization, improving mitochondrial function, and reducing oxidative stress. Transcriptomic and ultrastructural analyses identified that ELA potently suppressed pathological mitophagy. Mechanistically, ELA promoted FOXO3A lactylation, thereby preventing its nuclear translocation and promoting its cytoplasmic retention and degradation. Consequently, the mitophagy receptor BNIP3 expression was downregulated, thereby inhibiting excessive mitophagy. The anti-mitophagic effect of ELA was abrogated following genetic ablation of <i>Crebbp</i>, an enzyme reported with lactyltransferase capability.</p> Conclusion <p>Our findings demonstrate that ELA alleviates PCABI by dually reprogramming energy metabolism and suppressing pathological mitophagy. These results position lactate not only as a metabolite intermediate but also as a potential therapeutic agent and signaling molecule in PCABI.</p>

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Exogenous lactate administration alleviates post-cardiac arrest brain injury by coordinating metabolic reprogramming and pathological mitophagy suppression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Chenghao Wu,
  • Wenbin Zhang,
  • Yao Lin,
  • Minjie Lin,
  • Taiwen Rao,
  • Ziwei Chen,
  • Xiaodan Zhang,
  • Jiefeng Xu,
  • Mao Zhang

摘要

Background

The brain energy crisis following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is a major contributor to poor neurological outcomes. While lactate is traditionally viewed as a metabolic byproduct, its potential as an alternative metabolic substrate and as a signaling molecule remains controversial. This study investigates whether exogenous lactate administration (ELA) mitigates post-cardiac arrest brain injury (PCABI) and explores the underlying mechanisms.

Methods

A rat model of CA/CPR and HT22 neurons subjected to oxygen-glucose deprivation/reoxygenation were employed. Multi-omics profiling, metabolic flux analysis, immunofluorescence, transmission electron microscopy, co-immunoprecipitation, and gene knockdown, were employed to dissect the underlying mechanisms.

Results

ELA significantly improved 5-day survival, neurological function, and neuronal integrity in CA/CPR rats. Metabolomic and proteomic analyses revealed that ELA reprogrammed energy metabolism by alleviating the post-ischemic glycolytic surge, enhancing electron transport chain activity, and restoring the ATP/ADP ratio. In vitro, ELA’s neuroprotection was dependent on its cellular uptake and metabolic utilization, improving mitochondrial function, and reducing oxidative stress. Transcriptomic and ultrastructural analyses identified that ELA potently suppressed pathological mitophagy. Mechanistically, ELA promoted FOXO3A lactylation, thereby preventing its nuclear translocation and promoting its cytoplasmic retention and degradation. Consequently, the mitophagy receptor BNIP3 expression was downregulated, thereby inhibiting excessive mitophagy. The anti-mitophagic effect of ELA was abrogated following genetic ablation of Crebbp, an enzyme reported with lactyltransferase capability.

Conclusion

Our findings demonstrate that ELA alleviates PCABI by dually reprogramming energy metabolism and suppressing pathological mitophagy. These results position lactate not only as a metabolite intermediate but also as a potential therapeutic agent and signaling molecule in PCABI.