HCAR2 is a novel receptor for heme.

Extracellular heme, released during intravascular hemolysis in sickle cell disease (SCD) and hemolytic anemia, acts as a proinflammatory danger signal, requiring robust defense mechanisms. Previous studies identified G protein-coupled receptor (GPCR) signaling triggered by heme, but the specific receptor remained unknown. Transcriptomic analysis of bulk RNA sequencing of liver tissues from SCD and hemolytic mice (injection of phenylhydrazine) revealed GPCR signaling as a commonly enriched pathway. Unbiased screening of 241 GPCRs identified Hydroxycarboxylic Acid Receptor 2 (HCAR2/GPR109A), an anti-inflammatory receptor for niacin, as a novel heme sensor. Heme binding to human HCAR2 was validated using a functional reporter cell assay and direct interaction analyses via surface plasmon resonance and absorbance spectroscopy. In vivo, HCAR2 was upregulated in the liver of SCD and hemolytic mice, paralleling the expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). HO-1 inhibition or heme injection further increased HCAR2 expression, indicating that heme acts as both a ligand and an inducer of HCAR2. These findings identify HCAR2 as a novel heme receptor and reveal a heme-HCAR2-HO-1 negative feedback loop involved in tissue protection in hemolytic diseases.