Yijun Zhao, Yishan Li, Xiaobin Tian, Jingjing Guan, Yixin Ma, Xiaoqi Wang, Hongjian Zhang, Kaitao Wang, Kaizheng Jiang, Yalan Yang, Yuan Pan, Weiwei Liu, Xianzhe Hu, Jiafan Cao, Weiming Liu, Mengyun Xie, Kexin Sun, Jiayin Zheng, Ying Wang, Yucan Zheng, Yanjun Ling, Keyue Yang, Xuying Pei, Xiang-Yu Zhao, Xi Zhang, Pengxu Qian, Changzheng Li, Tian Lan, Linjia Jiang, Meng Zhao
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.