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  3. Correction of eIF4E overactivation rescues translatome imbalance and core ASD-like behaviors in valproic acid-induced offspring mice

Correction of eIF4E overactivation rescues translatome imbalance and core ASD-like behaviors in valproic acid-induced offspring mice

  • Mol Psychiatry. 2026 Mar 7. doi: 10.1038/s41380-026-03517-3.
Miaoqi Huang 1 2 3 4,  Han Ye 1 2,  Yong Xu 1 2,  Jiaoyan Xie 1 2,  Xinyu Wang 1 2,  Yan Luo 1 2,  Peng Liu 1 2,  Xuanyue Ma 1 2,  Shiqing Zhang 1 2,  Bin Jiang 3 4,  Wen-Cai Ye 5 6,  Yinghui Peng 7 8,  Lei Shi 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, 510632, China.
  • 2 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China.
  • 3 Medical College, Jiaying University, Meizhou, 514031, Guangdong, China.
  • 4 Guangdong Province Key Laboratory of Brain Function and Disease, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, 510632, China. [email protected].
  • 6 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China. [email protected].
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, 510632, China. [email protected].
  • 8 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China. [email protected].
  • 9 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, 510632, China. [email protected].
  • 10 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China. [email protected].
PMID: 41795048 DOI: 10.1038/s41380-026-03517-3
Abstract

Perturbed protein synthesis plays a crucial role in the pathogenesis of autism spectrum disorder (ASD), but the altered translational pattern and underlying mechanism remain poorly understood. Here, we identified an exaggeration of global protein synthesis in the cerebral cortex of offspring mice following prenatal exposure of valproic acid (VPA), a well-established ASD model. Integrative analysis of polyribosome-based translatome and proteome data revealed remarkable upregulation of ribosomal and mitochondrial genes in VPA-exposed cortex at both translational and protein levels, but not transcriptional levels. Further analysis pinpoints that overactivation of the translation initiation factor eIF4E causes the aberrant translatome and mitochondrial impairments in VPA-exposed cortex. Pharmacological inhibition of eIF4E phosphorylation during juvenile displayed persistent effectiveness in mitigating ASD-like social deficits and stereotyped behavior in VPA mice until adulthood. Collectively, these findings demonstrate that eIF4E overactivation leads to imbalanced protein synthesis that favors translation of ribosomal and mitochondrial genes, causing core ASD-like behaviors.

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