Novel Thrombopoietin-Mimetic Peptide 2B9F: A Promising Therapeutic Candidate for Hematopoietic Acute Radiation Syndrome.

Therapeutic interventions for hematopoietic acute radiation syndrome (H-ARS) remain limited in both variety and efficacy, falling short of achieving durable recovery of the hematopoietic system. Here, we develop 2B9F, a novel thrombopoietin-mimetic peptide engineered for enhanced stability and designed with the intention of achieving low immunogenicity. A single subcutaneous dose of 2B9F administered postexposure achieved complete survival in a lethal murine irradiation model, surpassing the efficacy of the clinically approved agent romiplostim. Treatment with 2B9F accelerated the recovery of peripheral blood counts and bone marrow nucleated cells, expanded functional hematopoietic stem cells (HSCs), and enhanced both in vitro clonogenic potential and in vivo competitive repopulation capacity. Mechanistic studies revealed that 2B9F promoted HSC quiescence and survival through transcriptional modulation of apoptosis and cell-cycle regulators. Importantly, a single low dose of 2B9F also conferred durable protection, mitigating delayed bone marrow suppression for up to six months postirradiation. These findings position 2B9F as a promising single-dose, low-immunogenicity therapeutic candidate for H-ARS, indicating strong potential for clinical translation in nuclear emergencies.