Back

Glutathione Protects Hematopoietic Stem Cells from Proteotoxic Stress

Paul, A.; Tom, H.; Merchant, S.; Phan, J.; Lemoff, A.; Mathews, T. P.; Karner, C. M.; Hoxaj, G.; Zhao, Z.; Morrison, S. J.

2026-10-06 cell biology
10.64898/2026.10.05.756790 bioRxiv
Show abstract

Glutathione is a redox buffer, best known for preventing oxidative stress and ferroptosis, but rarely studied in stem cells. We studied glutathione function in hematopoietic stem cells (HSCs) by deleting the glutamate-cysteine ligase catalytic subunit (GCLC), which synthesizes glutathione, or glutathione peroxidase 4 (GPX4), which employs glutathione to prevent ferroptosis. GCLC deficiency eliminated glutathione from hematopoietic cells, severely impairing HSC function and hematopoiesis. In contrast, GPX4 deficiency did not affect HSC function and had little effect on hematopoiesis, even after vitamin E depletion, suggesting glutathione has ferroptosis-independent functions in HSCs. Consistent with this, GCLC deficiency increased reactive oxygen species levels in hematopoietic cells. But treatment with antioxidants or ferroptosis inhibitors gave little or no rescue of HSC function despite reducing ROS levels. Rather, GCLC-deficient, but not GPX4-deficient, HSCs exhibited unfolded protein accumulation, proteostatic stress, and cell death marked by elevated p53 levels and Annexin V staining. Deficiency for p53 prolonged the function of GCLC-deficient HSCs after transplantation. Glutathione is thus necessary in HSCs for proteostasis but may be dispensable for ferroptosis inhibition in vivo.

Matching journals

The top 10 journals account for 50% of the predicted probability mass.

1
Stem Cell Reports
○ 130 papers in training set
Top 0.2%
12.6%
Similar papers in this journal
2
Stem Cells
◐ 31 papers in training set
Top 0.1%
7.2%
Similar papers in this journal
3
EMBO Reports
○ 263 papers in training set
Top 0.4%
6.2%
Similar papers in this journal
4
eLife
● 5828 papers in training set
Top 24%
5.1%
Similar papers in this journal
5
Scientific Reports
○ 3612 papers in training set
Top 26%
4.0%
6
Nature Communications
○ 5641 papers in training set
Top 33%
4.0%
Similar papers in this journal
7
Experimental Hematology
○ 11 papers in training set
Top 0.1%
3.2%
8
Biology Open
● 156 papers in training set
Top 0.8%
3.1%
9
Haematologica
● 25 papers in training set
Top 0.3%
2.8%
10
Redox Biology
○ 70 papers in training set
Top 0.4%
2.6%
50% of probability mass above
11
PLOS ONE
● 5266 papers in training set
Top 43%
2.1%
12
iScience
○ 1154 papers in training set
Top 13%
2.1%
13
Blood Advances
● 62 papers in training set
Top 0.7%
2.1%
14
Cell Death & Disease
147 papers in training set
Top 1%
2.1%
15
Proceedings of the National Academy of Sciences
● 2444 papers in training set
Top 26%
1.9%
16
Communications Biology
○ 993 papers in training set
Top 14%
1.7%
17
Blood
● 74 papers in training set
Top 0.8%
1.7%
18
Molecular and Cellular Biology
○ 47 papers in training set
Top 0.4%
1.5%
19
Biochemical and Biophysical Research Communications
○ 84 papers in training set
Top 1%
1.4%
20
The Journal of Immunology
◐ 166 papers in training set
Top 2%
1.3%
21
JCI Insight
● 277 papers in training set
Top 5%
1.3%
22
Stem Cell Research
○ 16 papers in training set
Top 0.2%
1.1%
23
Cell Stress and Chaperones
○ 11 papers in training set
Top 0.1%
1.1%
24
Frontiers in Cell and Developmental Biology
○ 233 papers in training set
Top 4%
1.1%
25
Biomolecules
○ 100 papers in training set
Top 2%
1.1%
26
Science Advances
● 1243 papers in training set
Top 28%
1.0%
27
Development
● 497 papers in training set
Top 4%
1.0%
28
Life Science Alliance
● 285 papers in training set
Top 6%
1.0%
29
Cell Stem Cell
○ 62 papers in training set
Top 2%
0.8%
30
Cell Reports
○ 1498 papers in training set
Top 27%
0.8%

"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.