Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling
Aging of hematopoietic stem cells (HSCs) impairs hematopoietic regeneration and differentiation, contributing to immune aging, systemic inflammation, and reduced lifespan. Strategies to rejuvenate aged HSCs and restore immune homeostasis remain limited. Here, we identify ferroptotic stress as a key contributor to HSC aging. Mechanistically, increased sphingosine metabolism elevates sphingosine-1-phosphate (S1P), which suppresses HDAC activity and enhances H3K9 acetylation to upregulate lysophosphatidylcholine acyltransferase 2 (Lpcat2), thereby promoting the accumulation of pro-ferroptotic phospholipids in aged HSCs. Genetic or pharmacological inhibition of sphingosine kinase 2 (Sphk2) reduces S1P levels, suppresses Lpcat2 expression, and attenuates ferroptotic stress in aged mouse and human HSCs. Notably, Sphk2 inhibition improves HSC function, restores immune homeostasis, and modestly extends lifespan in aged mice. Together, these findings identify an S1P-HDAC-Lpcat2 pathway linking epigenetic and lipid remodeling to ferroptotic stress and highlight sphingosine metabolism as a therapeutic target for HSC aging.
Authors
- Pengxu Qian (ORCID: https://orcid.org/0000-0001-5636-6704)
- Yuan Pan (ORCID: https://orcid.org/0000-0002-4058-1538)
- Kaitao Wang
- Lü Tian (ORCID: https://orcid.org/0000-0002-5893-0169)
- 裵緖英
- Linjia Jiang (ORCID: https://orcid.org/0000-0001-8854-2610)
- Yishan Li
- Xiaobin Tian (ORCID: https://orcid.org/0000-0002-3811-8413)
- Xiang‐Yu Zhao (ORCID: https://orcid.org/0000-0002-8139-1773)
- Meng Zhao (ORCID: https://orcid.org/0000-0001-6392-4954)
- Kaizheng Jiang
- Jiayin Zheng (ORCID: https://orcid.org/0000-0002-5559-6847)
- Y. Zhao
- Jingjing Guan (ORCID: https://orcid.org/0000-0001-8020-2398)
- Xi Zhang (ORCID: https://orcid.org/0000-0002-8548-2832)
- Yucan Zheng
- Hongjian Zhang (ORCID: https://orcid.org/0000-0003-1720-4280)
- Changzheng Li (ORCID: https://orcid.org/0000-0002-6226-5843)
- Yixin Ma (ORCID: https://orcid.org/0000-0003-0894-5909)
- Jiafan Cao
- Xianzhe Hu
- Yanjun Ling
- Keyue Yang
- Mengyun Xie
- Ying Wang
- Kexin Sun
- Xiaoqi Wang
- Yalan Yang
- Weiwei Liu
- Weiming Liu
Institutions
- Army Medical University (CN)
- Harbin Medical University (CN)
- Sun Yat-sen University (CN)
- Peking University (CN)
- Sun Yat-sen Memorial Hospital (CN)
- Xinqiao Hospital (CN)
- Peking University People's Hospital (CN)
- Zhejiang University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Blood
- Published
- 2026-08-24
- DOI
- https://doi.org/10.1182/blood.2026034204
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 0.00