Human-porcine transcriptomics reveals resuscitation-responsive pathways in trauma shock

Abstract Haemorrhage is the leading preventable cause of trauma death, primarily through ischaemic consequences that current treatments cannot adequately address. We combined human transcriptomic data (n=458) with a controlled porcine model of haemorrhagic shock to identify treatment-responsive molecular mechanisms. Using latent factorisation, we prioritised distinct molecular signatures of the human shock response, including stress signalling, neutrophil activation, and cytotoxic lymphocyte programmes. We assessed the behaviour of these pathways in the experimental porcine system, revealing that shock-initiated immune trajectories are not immutable: blood resuscitation normalised maladaptive transcriptomic changes whilst noradrenaline exacerbated them. While resuscitation modulated neutrophil, heat-shock, and barrier defence programmes, interferon and coagulation pathways were neither mortality-predictive nor treatment-responsive. A factor representing p38-MAPK/AP-1 stress signalling emerged as the dominant mortality-predictive pathway. An in silico small molecule screen identified p38 inhibitors as leading candidates for reversing shock-induced transcriptomic signatures. Our framework identifies modifiable pathways in trauma shock, prioritising p38-MAPK inhibition for therapeutic development and providing a systematic approach for trauma drug repurposing. One sentence summary : Human-porcine cross-analysis reveals treatment-modifiable molecular signatures of trauma shock, identifying potential therapeutic strategies.