Heme Iron Polypeptide Resolves Iron-deficiency Anemia in Rats and Mice

Dietary iron exists mainly as non-heme iron (NHI) and heme iron (HI). Mechanisms of NHI absorption have been recently revealed, but details of HI absorption remain uncertain. Heme is likely absorbed by receptor-mediated endocytosis, but to date, no receptor (or transporter) has been identified. Within enterocytes, heme may be catabolized by heme oxygenase in the ER, thus liberating ionic iron that then joins the labile cytosolic iron pool. One limiting factor in HI absorption research has been the lack of tractable experimental models. We addressed this shortcoming by establishing a nutritional paradigm that enables investigation of this process using pre-clinical rat and mouse models (JCI Insight. 2025;10(11):e184742). The approach utilized specially formulated diets containing lyophilized porcine RBCs that contained ~ 85% HI and 15% NHI. We have expanded upon these studies here to include heme iron polypeptide (HIP) as an iron source (Proferrin; Colorado Biolabs). HIP, a partially proteolyzed form of hemoglobin, is highly enriched for HI (~ 93% HI, 7% NHI). We again utilized a classic depletion/repletion experimental design in SD rats and C57BL/6 mice to compare outcomes when using three AIN-93-based test diets with ~ 50 ppm total iron: a HIP diet, a NHI diet containing FeSO4 and a HI-enriched diet formulated with porcine RBCs. Outcomes notably showed that all three experimental diets similarly corrected the anemia and normalized erythropoietic biomarkers in iron-depleted rats and mice within the 24-28-day test periods. These results solidify the concept that laboratory rodents are useful in vivo models to study intestinal HI absorption and utilization.