ABSTRACT This proposal aims to investigate the impact of sex as a biological variable (SABV) in the pathophysiology, biodosimetry, and treatment of radiation injury. Current research lacks exploration of sex differences, including the influence of gonadal hormones and sex chromosomes in hematopoietic (H-) and gastrointestinal (GI-) acute radiation syndromes (ARS) and its long-term effects (DEARE). The study highlights the importance of understanding these factors for gender-equitable medicine in radiation medical countermeasures. Initial data shows increased male mortality in response to radiation, and metabolomic differences based on SABV. The alarmin IL-33 has been shown in preliminary data and literature to exhibit sex-specific pleiotropic activation after injury. To discern the roles of hormones and sex chromosomes, a four core genotypes (FCG) mouse model is proposed, involving the deletion and relocation of the Sry gene. We hypothesize that SABV contributes to radiation damage response and regeneration and sexual dimorphism in IL-33-mediated immune responses in bone marrow and GI injury. This study will evaluate survival, histology, metabolomics, and transcriptomics in male and female wild type mice, gonadectomized mice, FCG mice, and IL-33 modulated mice. This research will provide insights into SABV in H-ARS and GI-ARS pathophysiology and inform potential novel therapies.