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Introduction O-GlcNAcylation (O-GlcNAc) is a dynamic post-translational modification involved in numerous cellular processes, including the response to cell stress and survival. It is regulated by a unique enzyme pair: O-GlcNAc transferase, which adds the GlcNAc moiety, and O-GlcNAcase (OGA), which removes it. Pharmacological inhibition of OGA with agents such as NButGT increases intracellular O-GlcNAc levels. Previous results from our laboratory demonstrated its benefit in rats subjected to haemorrhagic shock. 1 This study aimed to assess whether NButGT administration influences haemodynamic parameters during the early phase of haemorrhagic shock in a large mammalian model.Materials and Methods Twenty female Large White pigs (mean age: 4 months) were subjected to a traumatic haemorrhagic shock protocol, comprising bilateral femoral fractures, large muscular contusions and passive exsanguination of 60% of the estimated total blood volume (ETBV) via a jugular catheter. Animals were randomised to receive intramuscular NButGT (10 mg/kg; n = 9) or placebo (n = 8) immediately after exsanguination and again at 90 minutes following the defined time point of 40% ETBV drainage (T0). A control whole blood group (n = 3) underwent retransfusion at T120 min. Continuous haemodynamic monitoring was performed using the PiCCO system. Blood samples were collected at defined intervals, and tissue samples were obtained post-mortem. All procedures concluded with euthanasia six hours after T0.Results NButGT administration led to an increase in O-GlcNAcylation levels in cardiac tissue compared to placebo. No statistically significant difference in overall premature mortality was observed between groups (3 animals for NButGT and placebo groups); however, among the three premature deaths in each group, the mean time to death was 2 h 20 min in control animals and 3 h 00 min in NButGT-treated animals (non-significant difference). Cardiac output was significantly higher in the NButGT group at T90 min (p<0.05), and remained elevated at T120 min, although this did not reach statistical significance ( figure 1). Arterial and venous lactate concentrations did not differ significantly between groups.Discussion The observed increase in cardiac O-GlcNAc levels following NButGT administration, together with the associated rise in cardiac output, suggests a beneficial effect of NButGT on cardiac function during the acute phase of haemorrhagic shock. The absence of a significant effect on lactate levels supports the hypothesis that enhanced vascular distribution improves tissue perfusion, thereby increasing the proportion of adequately vascularised tissue and facilitating more efficient lactate clearance from these regions into the venous circulation. Although survival was not a primary endpoint, the longer time to death observed among the three premature fatalities in the treated group may indicate a potential survival benefit, which warrants further investigation.Conclusion This study demonstrates that pharmacological enhancement of O-GlcNAcylation via NButGT improves cardiac output in a porcine model of the acute phase of traumatic haemorrhagic shock. The potential impact on short-term survival now merits further exploration. These findings, reported here for the first time in a large mammal, support continued investigation into inhibition of OGA as a potential adjunct therapy. Future studies should include extended observation periods and the assessment of tissue perfusion markers to better elucidate the therapeutic potential and underlying mechanisms. Inhibition of OGA is not intended to serve as a stand-alone treatment for haemorrhagic shock; however, it may represent a promising adjuvant strategy, capable of prolonging the survival window and allowing patients to reach definitive care in a medical facility.Abstract P04 Figure 1Mean of cardiac output at each time (Picco monitoring). Error intervals: standard error. * : p-value < 0,05 of unpaired unilateral Student’s t-test between NButGT and Placebo (alternative hypothesis NButGT > Placebo). n =20Reference Vergnaud A, Dupas T, Aillerie V, et al. Sodium potassium pump: a novel O-GlcNAc protein beneficial in hemorrhagic shock situation. Arch Cardiovasc Dis. 2024;117:S55. https://doi.org/10.1016/j.acvd.2023.10.100.Disclosure with Conflicts of Interest The authors have no conflicts of interest to declare.approval by sponsoring authority: French armed forces