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Targeting the SIRT6-TDO2/KYNA-mTOR axis rescues synaptic and cognitive deficits in fetal growth restriction offspring

Shujuan Chang1, Wen Chen2, Wei Zhu1

  • 1Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China.

Experimental & Molecular Medicine
|June 11, 2026
PubMed

Insights

Fetal growth restriction causes cognitive deficits by reducing SIRT6, which impairs synaptic function. Restoring SIRT6 or targeting the kynurenine pathway can reverse these impairments in offspring.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Metabolic Disorders

Background:

  • Fetal growth restriction (FGR) is linked to lifelong cognitive deficits.
  • The precise molecular mechanisms underlying FGR-induced cognitive impairments are not fully understood.

Purpose of the Study:

  • To identify the key molecular pathways mediating synaptic dysfunction and cognitive deficits in FGR offspring.
  • To investigate the role of the SIRT6-TDO2/KYNA-mTOR axis in FGR-associated neurodevelopmental issues.

Main Methods:

  • Utilized a mouse model of FGR and conditional knockout of SIRT6 in specific neuronal populations.
  • Investigated the impact of SIRT6 deficiency on synaptic plasticity, cognitive performance, and hippocampal kynurenic acid (KYNA) levels.
  • Examined the effects of pharmacological and genetic interventions targeting the TDO2/KYNA and mTOR pathways.

Main Results:

  • Reduced SIRT6 expression in FGR mice led to synaptic dysfunction and cognitive deficits.
  • SIRT6 deficiency increased hippocampal KYNA by enhancing kynurenine pathway flux, suppressing mTOR signaling and synaptic protein synthesis.
  • Targeting TDO2 or activating mTOR reversed synaptic and cognitive impairments in Sirt6-deficient mice.
  • SIRT6 overexpression in FGR mice normalized KYNA, restored mTOR signaling, and improved cognitive function.

Conclusions:

  • The SIRT6-TDO2/KYNA-mTOR axis is a critical mediator of synaptic and cognitive deficits in FGR.
  • Neuronal SIRT6 deficiency dysregulates tryptophan metabolism, impairing synaptic plasticity and cognitive performance.
  • This axis presents potential therapeutic targets for treating cognitive disorders associated with FGR.

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