Sex-Associated Proteomic Signatures Persist Independent of Injury Severity and Shock Physiology in Acute Trauma

BACKGROUND: Sex-based differences in trauma outcomes are well documented, but the early molecular programs distinguishing male and female responses remain incompletely defined. We hypothesized that biological sex shapes the circulating proteomic and metabolomic response at emergency department arrival and that these signatures interact with age, injury severity, and shock physiology. METHODS: Patients meeting the highest level of trauma activation criteria were prospectively enrolled. Blood samples were collected upon arrival to the emergency department within one hour of injury and before transfusion. Plasma proteomics and metabolomics were performed by liquid chromatography-mass spectrometry. Sex differences were assessed by feature-level testing with Benjamini-Hochberg FDR correction. Multivariable linear models adjusted for age, ISS, base deficit, lactate, mechanism, and head/neck injury. Spearman correlations and network visualization integrated omics and clinical variables. RESULTS: Among 292 patients (236 male, 56 female), baseline characteristics were similar. Unadjusted analyses identified 45 proteins and 9 metabolites differing by sex. Female-enriched proteins included PZP, CERU, SHBG, VTNC, ITIH3, and IGHM; male-enriched included FCN3, AMPN, APOD, GELS, NCAM1, ANTR2, MASP1, and GPX3. After adjustment, sex remained independently associated with FCN3, SHBG, PTPRG, CERU, FUCO, PZP, and APOD. Sex-associated metabolite differences were more strongly coupled to injury severity and shock physiology than to sex alone. CONCLUSION: Male and female trauma patients demonstrate distinct early multi-omic signatures, including sex-associated immune, complement, redox, and metabolic programs that persist after adjustment for injury severity and shock physiology. Sex-informed omics may improve biological endotyping and precision approaches to trauma care.