Omics-guided therapeutic translation in acute traumatic brain injury

Decades of trials evaluating secondary-injury targeted therapeutics in traumatic brain injury (TBI) have failed almost without exception, typically concluding that the intervention was ineffective. We argue that these failures stem largely from methodological limitations and should be reconceptualized. TBI pathobiology has traditionally been studied, stratified, and treated using single markers, isolated mechanisms, and discrete timepoints, despite being heterogeneous, compartmentalized, and temporally dynamic. High-dimensional omics, interpreted at the level of biological pathways rather than individual analytes, offers a direct means of addressing this complexity. Focusing on the acute phase of moderate-to-severe TBI, we define four recurrent failure modes in TBI therapeutic translation: the wrong patient, the wrong sample, the wrong window, and the wrong mechanism. For each, we identify targeted omics and pathway-level strategies that can mitigate these limitations and summarize what such approaches have revealed about TBI pathobiology. Finally, we argue that pathway-based predictive enrichment, combined with drug repurposing, is a promising near-term strategy that may improve the odds of detecting a real treatment effect where unselected trials have not.