Ferroptosis regulates hemolysis in stored murine and human red blood cells

作者：Angelo D’Alessandro, Gregory R. Keele, Ariel Hay, Travis Nemkov, Eric J. Earley, Daniel Stephenson, Matthew Vincent, Xutao Deng, Mars Stone, Monika Dzieciątkowska, Kirk C. Hansen, Steven Kleinman, Steven L. Spitalnik, Nareg H. Roubinian, Philip J. Norris, M. Busch, Grier P. Page, Brent R. Stockwell, Gary A. Churchill, James C. Zimring · 发表于：Blood · 年份：2024 · DOI：10.1182/blood.2024026109 · 被引用次数：45 · 研究领域：Hemoglobinopathies and Related Disorders、Epigenetics and DNA Methylation、Erythrocyte Function and Pathophysiology

ABSTRACT: Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. On the basis of the breeding of 8 founder strains with extreme genetic diversity, the Jackson Laboratory diversity outbred population can capture the impact of genetic heterogeneity in like manner to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for posttransfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid quantitative trait loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase 6-transmembrane epithelial antigen of the prostate 3 (Steap3), a transcriptional target to p53. Steap3 regulated posttransfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation, and in vitro hemolysis in 13 091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (fatty acid desaturases 1 and 2, epoxide hydrolas...