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SENP1 inhibits aerobic glycolysis in Aβ1-42-incubated astrocytes by promoting PUM2 deSUMOylation
Qianshuo Liu, Meixi Jiang, Zening Wang, Jihong Meng, Hui Jia, Jing Li, Jing‐Jer Lin, Libin Guo et al.. Cell Biology and Toxicology, 2025-01-10
Topic: Brain proteins, microglia and lab models
Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly, involves critical changes such as reduced aerobic glycolysis in astrocytes and increased neuronal apoptosis, both of which are significant in the disease’s pathology. In our study, astrocytes treated with amyloid β1-42 (Aβ1-42) to simulate AD conditions exhibited upregulated expressions of small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) and Pumilio RNA Binding Family Member 2 (PUM2), alongside decreased levels of Nuclear factor erythroid 2-related factor 2 (NRF2). SENP1 is notably the most upregulated SUMOylation enzyme in Aβ1-42-exposed astrocytes. Functional assays including Ni2+-Nitrilotriacetic acid (NTA) agarose bead pull-down and co-immunoprecipitation (Co-IP) confirmed SENP1’s role in actively deSUMOylating PUM2, thereby enhancing its stability and expression. The interaction between PUM2 and the 3’ untranslated region (3’UTR) of NRF2 mRNA reduces NRF2 levels, subsequently diminishing the transcriptional activation of critical glycolytic enzymes, Hexokinase 1 (HK1) and Glucose Transporter 1 (GLUT1). These changes contribute to the observed reduction in glycolytic function in astrocytes, exacerbating neuronal apoptosis. Targeted interventions, such as knockdown of Senp1 or Pum2 or overexpression of NRF2 in APPswe/PSEN1dE9 (APP/PS1) transgenic mice, effectively increased HK1 and GLUT1 levels, decreased apoptosis, and alleviated cognitive impairment. These findings highlight the important roles of the SENP1/PUM2/NRF2 pathway in influencing glucose metabolism in astrocytes, presenting new potential therapeutic targets for AD. 1. SENP1 deSUMOylates PUM2 enhancing its expression in Aβ1-42-microenvironment. 2. PUM2 binds to NRF2 mRNA reducing its stability and expression in Aβ1-42-microenvironment. 3. Reduced NRF2 reduces its transcriptional promoting effects on HK1 and GLUT1 in Aβ1-42-microenvironment. 4. Reduced HK1 and GLUT1 decreases aerobic glycolysis in astrocytes, leading to an increase in co-culture neuronal apoptosis in Aβ1-42-microenvironment.
Key findings
- Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly, involves critical changes such as reduced aerobic glycolysis in astrocytes and increased neuronal apoptosis, both of which are significant in the disease’s pathology.
- These findings highlight the important roles of the SENP1/PUM2/NRF2 pathway in influencing glucose metabolism in astrocytes, presenting new potential therapeutic targets for AD. 1.
Why it matters
In astrocytes exposed to amyloid-beta in the laboratory, the SENP1/PUM2/NRF2 pathway reduced glycolysis and increased neuronal apoptosis, and targeting this pathway in transgenic mice increased glycolytic enzymes. These are early cell and animal findings that identify potential targets, not a proven treatment.
Study details
- Evidence strengthLow
How this study scored 38/100
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. We have no data on senior author's track record, so that was left out: it earned 36 of the 96 points we could judge it on, which is 38 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cell Biology and Toxicology) |
| Journal's citation record | 1 / 4 | Cell Biology and Toxicology: journal h-index 95 (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 7 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.8× 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 7 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 0 / 3 | Chinese PLA General Hospital: institution h-index 413 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39794619) |
| Free to read | 2 / 2 | Free to read |
| Points | 36 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 36 of the 96 points we could judge it on is 38 out of 100. |
| Total | 38 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1007/s10565-025-09986-6
- PubMed: 39794619
- Original source →
- Free full text: Cell Biology and Toxicology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Liu, Q., Jiang, M., Wang, Z., Meng, J., Jia, H., Li, J., et al. (2025). SENP1 inhibits aerobic glycolysis in Aβ1-42-incubated astrocytes by promoting PUM2 deSUMOylation. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-025-09986-6
Vancouver
Liu Q, Jiang M, Wang Z, Meng J, Jia H, Li J, et al. SENP1 inhibits aerobic glycolysis in Aβ1-42-incubated astrocytes by promoting PUM2 deSUMOylation. Cell Biology and Toxicology. 2025. doi:10.1007/s10565-025-09986-6. PMID: 39794619.
BibTeX
@article{liu2025-39794619,
author = {Liu, Qianshuo and Jiang, Meixi and Wang, Zening and Meng, Jihong and Jia, Hui and Li, Jing and Lin, Jing‐Jer and Guo, Libin and others},
title = {{SENP1 inhibits aerobic glycolysis in Aβ1-42-incubated astrocytes by promoting PUM2 deSUMOylation}},
journal = {Cell Biology and Toxicology},
year = {2025},
doi = {10.1007/s10565-025-09986-6},
pmid = {39794619},
url = {https://doi.org/10.1007/s10565-025-09986-6}
}
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