Blood · 2026
Ferroptotic stress promotes hematopoietic stem cell aging through S1P-dependent epigenetic and lipid remodeling.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Zhao Yijun, Li Yishan, Tian Xiaobin, Guan Jingjing, Ma Yixin, Wang Xiaoqi, Zhang Hongjian, Wang Kaitao, Jiang Kaizheng, Yang Yalan, Pan Yuan, Liu Weiwei, Hu Xianzhe, Cao Jiafan, Liu Weiming, Xie Mengyun, Sun Kexin, Zheng Jiayin, Wang Ying, Zheng Yucan, Ling Yanjun, Yang Keyue, Pei Xuying, Zhao Xiang-Yu, Zhang Xi, Qian Pengxu, Li Changzheng, Lan Tian, Jiang Linjia, Zhao Meng
Аннотация
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.