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. 2021 Mar 12;12:1645. doi: 10.1038/s41467-021-21938-2

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — a Transient improvement with oral isocitrate monotherapy. Mean red cell count (RBC) in C57BL/6 mice ± anemia ± isocitrate treatment (600 mg/kg/dose) provided in three gavages every other day (arrows). Blue: healthy non-anemic control mice; red: mice with anemia of chronic disease and inflammation (ACDI) due to injection of killed Brucella abortus (KBA), treated with saline; green: mice with KBA ACDI treated with isocitrate. Error bars, SEM; n = 10/group for healthy and 9/group for both KBA; *, ***P = 0.047, 0.0036, one-way ANOVA with Dunnett correction using KBA saline control as reference. b Sustained improvement with oral low-dose fumarate plus isocitrate. Mean red cell count (RBC) in C57BL/6 mice ± KBA ACDI ± fumarate (Fum, 18.6 mg/kg/dose) ± isocitrate (IC, 150 mg/kg/dose) provided in five daily gavages (arrows). Blue: healthy controls; red: mice with KBA ACDI treated with fumarate alone; green: mice with KBA ACDI treated with isocitrate combined with fumarate. Error bars, SEM; n = 6/group for healthy and 10–12/group for both KBA; **, ***, ****P = 0.0036, 0.0003, 0.0001 one-way ANOVA with Tukey post hoc. c, d Enhancement of splenic erythropoietic maturation. Flow plots demonstrate maturation stages (I–V) for splenic nucleated Ter119+ erythroblasts from C57BL/6 mice with KBA ACDI treated with saline or isocitrate + fumarate (IC/F) as in b. FSC forward light scatter. Graph: mean % erythroblasts at indicated stages for healthy or anemic mice ± isocitrate and fumarate (IC/F). Error bars, SEM; n = 8/group for healthy, 9/group for KBA saline, and 10/group for KBA IC + Fum; *, ***P = 0.026, 0.0039, one-way ANOVA with Tukey post hoc. e Long-term correction of anemia with intermittent oral low-dose fumarate plus isocitrate. Mean RBC in C57BL/6 mice ± KBA ACDI ± fumarate (Fum, 18.6 mg/kg/dose) and isocitrate (IC, 150 mg/kg/dose) provided in five daily gavages (arrows) on the first week of each month. Blue: healthy controls; red: mice with KBA ACDI treated with saline; green: mice with KBA ACDI treated with isocitrate and fumarate. Error bars, SEM; n = 8–10/group for healthy; 7–9/group for KBA saline; 8–9/group for KBA IC + Fum; **, ****P = 0.002–0.0001 for all time points after day 0, one-way ANOVA with Tukey post hoc. f Model for potential mechanism of isocitrate–fumarate cooperation in amelioration of iron-restricted anemia. In this model, ferritin serves as a critical node, integrating signals from iron and metabolites and acting on key cytoskeletal functions. Green indicates positive influence, and red indicates negative influence. See also Supplementary Fig. 11. Source data are provided as a Source data file.