Hydrolyzed Milk-Derived Peptides Promote Erythropoietin Pathways and Hematologic Recovery: A Cross-Species Analysis

Anemia, characterized by reduced hemoglobin (Hb), remains a major health concern. Although iron and erythropoietin (EPO) therapies are effective, limitations in safety and accessibility have prompted interest in nutritional alternatives. Hydrolyzed milk-derived peptides (H-MDPs) contain bioactive sequences with diverse physiological effects, yet their role in erythropoiesis remains poorly defined. This study investigated the hematopoietic actions of H-MDP using zebrafish and mouse models. Adult zebrafish underwent phlebotomy-induced anemia and received oral H-MDP for 3 weeks. Hb levels, erythrocyte morphology, and expression of erythropoiesis- and iron-metabolism genes were assessed. In healthy mice, renal <i>Epo</i> expression, circulating EPO, and serum cytokines were measured after 2 weeks of H-MDP administration. H-MDP significantly accelerated Hb recovery in anemic zebrafish (4.6 ± 0.64 g/dL vs. 3.4 ± 0.66 g/dL in untreated fish at week 1) and markedly improved erythrocyte maturation. These effects coincided with strong induction of <i>epo</i>, <i>hif1aa/b</i>, <i>igf1</i>, <i>csf1a</i>, and <i>csf3b</i> in the heart and liver, as well as normalization of anemia-induced hepatic iron-transport genes (<i>tfa</i>, <i>fpn1</i>, <i>tfr2</i>) and reactivation of <i>hamp</i>. In mice, H-MDP elevated renal <i>Epo</i> mRNA and circulating EPO (approximately 2.3-fold) without altering steady-state Hb, and cytokine profiling with IPA-predicted activation of the erythropoietin signaling pathway. Collectively, these findings indicate that H-MDPs modulate erythropoiesis by coordinating the activation of EPO-related and iron-regulatory networks, supporting their potential as functional food ingredients for hematologic recovery and anemia management.