Seawater immersion reshapes the temporal dynamics of traumatic brain injury and reveals mitochondrial oxidative stress as a modifiable therapeutic target.
Traumatic brain injury (TBI) evolves through time-dependent secondary injury, but whether seawater (SW) immersion merely amplifies pathology or reshapes the temporal trajectory of post-traumatic biology remains unclear. Here, we applied time-resolved proteomics to mouse brains after controlled cortical impact (CCI) with or without artificial SW immersion at 1, 3, 7, and 28 days post-injury. Trajectory-based proteomic analysis revealed that SW immersion altered the direction, magnitude, timing, persistence, and recovery of protein responses, rather than simply intensifying TBI-induced changes. This remodeled trajectory exhibited phase-specific patterns, including SW-dominant, synergistically enhanced, and attenuated responses, highlighting mitochondrial oxidative stress, inflammatory activation, complement/coagulation disturbance, and impaired structural repair. Phenotypic validation confirmed phase-specific deficits, including acute inflammatory-redox injury, impaired neuronal survival, chronic axon-myelin disruption, and incomplete behavioral recovery. SS-31 partially mitigated selected inflammatory, redox, neuronal, and white matter abnormalities, supporting mitochondrial oxidative stress as a modifiable node rather than the sole driver of trajectory remodeling. These findings identify seawater immersion as a temporal modifier of secondary injury and emphasize that environmental trauma may require trajectory-informed, phase-specific therapeutic interventions.