Cholesterol confers ferroptosis resistance onto myeloid-biased hematopoietic stem cells and prevents irradiation-induced myelosuppression

• DOI: 10.1016/j.redox.2023.102661
• Publication Date: 2023-03-08T01:54:40Z
• Authors: Chaonan Liu; Weinian Liao; Jun Chen; Kuan Yu; Yiding Wu; Shuzhen Zhang; Mo Chen; Fang Chen; Song Wang; Tianmin Cheng; Junping Wang; Changhong Du
• Keywords: Hematopoietic stem cell

There is growing appreciation that hematopoietic alterations underpin the ubiquitous detrimental effects of metabolic disorders. The susceptibility bone marrow (BM) hematopoiesis to perturbations cholesterol metabolism well documented, while underlying cellular and molecular mechanisms remain poorly understood. Here we reveal a distinct heterogeneous signature within BM stem cells (HSCs). We further show directly regulates maintenance lineage differentiation long-term HSCs (LT-HSCs), with high levels intracellular favoring myeloid bias LT-HSCs. During irradiation-induced myelosuppression, also safeguards LT-HSC regeneration. Mechanistically, unravel distinctively enhances ferroptosis resistance boosts but dampens lymphoid Molecularly, identify SLC38A9-mTOR axis mediates sensing signal transduction instruct LT-HSCs as dictate sensitivity through orchestrating SLC7A11/GPX4 expression ferritinophagy. Consequently, myeloid-biased are endowed survival advantage under both hypercholesterolemia irradiation conditions. Importantly, mTOR inhibitor rapamycin inducer imidazole ketone erastin prevent excess cholesterol-induced HSC expansion bias. These findings unveil an unrecognized fundamental role in fate decisions valuable clinical implications.