HCAR2 is a novel receptor for heme Open Access

• Hydroxycarboxylic acid receptor 2 (HCAR2) is identified as a receptor for heme.

• Heme triggers HCAR2 expression in mice with sickle cell disease and intravascular hemolysis, which is regulated by HO-1.

Extracellular heme, released during intravascular hemolysis in sickle cell disease (SCD) and hemolytic anemia acts as a pro-inflammatory danger signal, requiring robust defense mechanisms. Previous studies identified GPCR signaling triggered by heme, but the specific receptor remained unknown. Transcriptomic analysis of bulk RNAseq 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.