Tuesday, August 19, 2025 8/19/2025

Heme-induced metabolic stress drives ferroptosis in sickle cell disease

Award Number: R01DK139694
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

Group Awards By:

View Award Description

Heme-induced metabolic stress drives ferroptosis in sickle cell disease - (PLEASE KEEP IN WORD, DO NOT PDF) Individuals with sickle cell disease (SCD) have severe anemia due to chronic red blood cell hemolysis and increased oxidative stress. SCD patients present abnormal metabolome profiling for metabolites involved in glycolysis, the tricarboxylic acid (TCA) cycle, nucleotide catabolism, and glutathione metabolism. As those metabolites are critical for the hypoxic response, contributing to RBC sickling, mediating inflammation, and activating oxidative stress response, it is warranted to characterize the mechanism by which those aberrant metabolic programs contribute to the SCD disease progression and severity. By metabolite profiling analysis, we demonstrate that excess heme exposure from hemolysis impairs the TCA cycle activity, leading to accumulated levels of 2-Oxoglutarate (2OG), which will outflow towards L-2-hydroxyglutarate (L2HG). The accumulated 2OG and L2HG display epigenetic modification functions through regulating the enzymatic activity of 2OG-dependent histone demethylases and induce histone hypermethylation. These aberrant epigenetic changes suppress the expression of genes involved in heme/iron metabolism and ferroptosis response and cause iron-dependent programmed cell death ferroptosis. Excess heme was also found to induce the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the oxidative stress response. Nrf2 ablation in SCD mouse model increased both L2HG levels and histone methylation to affect the expression of genes involved in oxidative and ferroptosis stress response. From these preliminary findings, we hypothesize that the Nrf2/hemin/L2HG signaling mediates an integrated metabolic, epigenetic, and ferroptotic response program to regulate SCD severity. We will test this hypothesis with two specific aims. Aim 1. To test the hypothesis that heme affects both metabolic and ferroptotic regulatory pathways to drive ferroptosis during erythropoiesis. Aim 2. To evaluate the therapeutic potential by modulating the Nrf2/hemin/L2HG signaling in preclinical SCD animal model. Findings from the studies will illustrate that the Nrf2/hemin/L2HG signaling integrates metabolic, epigenetic and ferroptotic programs to modulate the severity of SCD disease. Such signaling would be therapeutically exploitable for SCD treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $308,000 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/11/2025	NON-COMPETING CONTINUATION	$308,000
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $308,000

Issue Date FY: 2024 ( Subtotal = $295,680 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/21/2024	NON-COMPETING CONTINUATION	$295,680
														Subtotal = $295,680

Issue Date FY: 2023 ( Subtotal = $308,000 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2023	NEW	$308,000
														Subtotal = $308,000

Grand Total All Awards = $911,680

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Heme-induced metabolic stress drives ferroptosis in sickle cell disease

Award Number: R01DK139694

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/25/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer