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NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus
Daniel Carnicero-Senabre, Mariana Afonso Barata, José Jiménez-Villegas, Cláudia Guimas Almeida, Antonio Cuadrado, Ana Isabel Rojo. Redox Biology, 2025-08-30
Topic: Brain proteins, microglia and lab models
Synaptic loss is a key factor in the cognitive decline observed during aging and in neurodegenerative diseases such as dementia, where synaptopathy plays a central role in hippocampal dysfunction. In this study, we investigated the role of NRF2, a master regulator of cellular homeostasis, in maintaining synaptic integrity. We assessed synaptic contacts both in vitro and in vivo and found that NRF2 deficiency leads to a significant reduction in vGLUT1 levels, accompanied by a decrease in the number of synaptic contacts. Because synapses are subject to highly dynamic membrane remodeling processes, we analyzed the lipid composition of hippocampi and synaptosomes from NRF2-deficient and wild-type mouse littermates. Our results revealed an accumulation of ether-linked phospholipids in NRF2-deficient mice. When primary neuronal and organotypic cultures were exposed to an ether-lipid precursor, synaptic density decreased. By contrast, the NRF2 activator 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC or hexaraphane) prevented synaptic loss. Although ether lipids are abundant components of neuronal membranes, their specific role in synaptic function and in age-related loss of homeostatic balance remains poorly understood. This study is the first to demonstrate that NRF2 plays an essential role in preserving synaptic homeostasis through lipid metabolism, suggesting its relevance in the context of aging and neurodegenerative diseases.
Key findings
- We assessed synaptic contacts both in vitro and in vivo and found that NRF2 deficiency leads to a significant reduction in vGLUT1 levels, accompanied by a decrease in the number of synaptic contacts.
- Our results revealed an accumulation of ether-linked phospholipids in NRF2-deficient mice.
Why it matters
In mice and cell cultures, lack of NRF2 reduced synaptic contacts and caused accumulation of ether-linked phospholipids, while the NRF2 activator 6-MSITC prevented synaptic loss. This is early animal and laboratory work, and the authors say the role of ether lipids in synaptic function and age-related decline remains poorly understood.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Redox Biology) |
| Journal's citation record | 2 / 4 | Redox Biology: journal h-index 209 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Ana Isabel Rojo: h-index 45 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Edinburgh: institution h-index 1,378 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40902316) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Carnicero-Senabre, D., Barata, M. A., Jiménez-Villegas, J., Almeida, C. G., Cuadrado, A., & Rojo, A. I. (2025). NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus. Redox Biology. https://doi.org/10.1016/j.redox.2025.103853
Vancouver
Carnicero-Senabre D, Barata MA, Jiménez-Villegas J, Almeida CG, Cuadrado A, Rojo AI. NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus. Redox Biology. 2025. doi:10.1016/j.redox.2025.103853. PMID: 40902316.
BibTeX
@article{carnicerosenabre2025-40902316,
author = {Carnicero-Senabre, Daniel and Barata, Mariana Afonso and Jiménez-Villegas, José and Almeida, Cláudia Guimas and Cuadrado, Antonio and Rojo, Ana Isabel},
title = {{NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus}},
journal = {Redox Biology},
year = {2025},
doi = {10.1016/j.redox.2025.103853},
pmid = {40902316},
url = {https://doi.org/10.1016/j.redox.2025.103853}
}
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