CPEB1 drives ferroptosis-neuroinflammation crosstalk in temporal lobe epilepsy via the SIRT1-NRF2 acetylation axis.

Overview

1. Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
2. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
3. Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

Abstract

Background: Temporal lobe epilepsy (TLE) is a common neurological disorder frequently resistant to pharmacological treatment, yet its molecular mechanisms remain incompletely understood. Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is a post-transcriptional regulator implicated in neuronal stress responses; however, its role in epilepsy and redox-inflammatory signaling remains unclear.

Methods: An integrative multi-omics strategy combining single-cell transcriptomics, bulk RNA sequencing, and bioinformatics analyses was employed, followed by validation in human epileptic hippocampal tissues, kainic acid (KA)- and pentylenetetrazol (PTZ)-induced mouse models, as well as in vitro glutamate-induced neuronal injury models. Mechanistic investigations were performed using adeno-associated virus (AAV)-mediated CPEB1 overexpression and knockdown, together with pharmacological modulation of the SIRT1 and NRF2 pathways.

Results: CPEB1 was markedly upregulated in neurons from both TLE patients and experimental models. Neuronal overexpression of CPEB1 increased seizure susceptibility, exacerbated neuronal loss, and promoted oxidative stress, proinflammatory cytokine release, and ferroptosis, whereas CPEB1 knockdown exerted robust neuroprotective effects. Mechanistically, CPEB1 suppressed SIRT1 activity, leading to enhanced acetylation-dependent destabilization of NRF2, impaired downstream SLC7A11/GPX4 antioxidant signaling, and excessive reactive oxygen species (ROS) accumulation, ultimately triggering ferroptotic neuronal death. Importantly, pharmacological inhibition of SIRT1 or NRF2 abolished the neuroprotective effects of CPEB1 knockdown, confirming the critical role of the CPEB1–SIRT1–NRF2 acetylation axis in TLE pathogenesis.

Conclusion: CPEB1 aggravates neuronal injury in TLE by driving ferroptosis–neuroinflammation crosstalk through suppression of the SIRT1–NRF2 acetylation axis. Targeting this pathway may provide a promising therapeutic strategy for drug-resistant epilepsy and related neurodegenerative disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE256068, at NCBI GEO; found in “Data availability statement”

Data availability statement

The scRNA-seq data used in this study are available in the Gene Expression Omnibus (GEO) repository under accession number GSE190452 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE190452). The bulk RNA-seq data are deposited in the GEO repository under accession number GSE256068 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE256068). All other data generated or analyzed during this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 8 authors, 6 keywords, 17 MeSH terms, 62 references.

Cite

This paper

Huang, C., You, Z., Gao, X., He, Y., Zhao, S., Fan, Z., Wei, F., & Sun, J. (2026). CPEB1 drives ferroptosis-neuroinflammation crosstalk in temporal lobe epilepsy via the SIRT1-NRF2 acetylation axis. Frontiers in immunology, 17, 1727784. https://doi.org/10.3389/fimmu.2026.1727784

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