BACKGROUND: It is well-known that hematopoietic cells are sensitive to irradiation exposure. Apoptosis, necroptosis, pyroptosis and ferroptosis might contribute to irradiation-induced hematopoietic injury. However, it is uncertain whether different hematopoietic cells apply specific cell death pathways under irradiation exposure. METHODS: We investigated the role of different programmed cell death pathways in irradiation-induced hematopoietic cell injury. In order to study the acute and long-term effects of ionizing radiation on hematopoietic system, we established injury models of mice at different time points after irradiation and measured the proportion of hematopoietic stem progenitor cells by flow cytometry. The pattern of programmed cell death involved in radiation-induced hematopoietic cell injury was identified through the analysis of different populations of hematopoietic cells in the bone marrow by immunomagnetic bead sorting combined with qRT-PCR and flow cytometry. The role of pyroptosis in radiation injury of hematopoietic stem cells was further studied by Caspase-1 inhibitor VX-765 application. In vivo spleen colony formation, competitive bone marrow transplantation and secondary transplantation were used to verify the protective effect of inhibiting Caspase-1 on hematopoietic stem cells damaged by radiation. RNA sequencing (RNA-Seq) using Linc-Kit cell populations revealed the mechanism by which inhibition of Caspase-1 mitigates post-irradiation hematopoietic stem cell damage. RESULTS: A single exposure to whole-body ionizing radiation of 3 Gy causes acute bone marrow injury and long-term myelosuppression, resulting in hematopoietic imbalances and a bias toward myeloid differentiation. Ionizing radiation induced bone marrow B cell apoptosis and necroptosis, bone marrow T cell apoptosis. Various programmed cell death modes were involved in radiation injury of hematopoietic stem cells. Inhibition of Caspase-1 by VX-765 accelerated the recovery of hematopoietic stem cells after radiation. It is worth noting that inhibition of Caspase-1 promotes the proliferation and differentiation of hematopoietic stem cells after ionizing radiation. VX-765 treatment under ionizing radiation stress increased numbers of spleen colony formation, ability of long-term hematopoietic reconstitution in vivo and self-renewal. VX-765 alleviates post-irradiation hematopoietic stem cell injury by inhibiting pyroptosis, apoptosis and necroptosis. CONCLUSIONS: These data suggest that multiple programmed cell death pathways are involved in radiation-induced damage to hematopoietic cells. Inhibiting Caspase-1 activity can be used as a strategy for protecting against radiation-induced injury to hematopoietic stem cells.