Experimental study demonstrates that inhibiting Sphk2 reduces ferroptosis and restores hematopoietic stem cell function in aged mice, highlighting a therapeutic target for immune aging.
Key Points
Investigate the role of ferroptotic stress and sphingosine metabolism in hematopoietic stem cell aging and determine whether targeting this pathway can rejuvenate aged cells.
Analyzed sphingosine metabolism, HDAC activity, H3K9 acetylation, and Lpcat2 expression in aged mouse and human hematopoietic stem cells (HSCs).
Tested the effects of genetic and pharmacological inhibition of sphingosine kinase 2 (Sphk2) on ferroptotic stress, HSC function, immune homeostasis, and lifespan in aged mice.
Elevated S1P in aged HSCs suppressed HDAC activity and increased H3K9 acetylation to upregulate Lpcat2, driving pro-ferroptotic phospholipid accumulation.
Inhibition of Sphk2 lowered S1P levels and Lpcat2 expression, significantly attenuating ferroptotic stress in both mouse and human aged HSCs.
Sphk2 blockade improved aged HSC regenerative capacity, restored immune homeostasis, and modestly extended lifespan in aged mice.