A robust coordinated molecular response following trauma promotes recovery and protects against chronic pain and neuropsychiatric symptoms

The biological mechanisms governing recovery versus chronicity of adverse posttraumatic neuropsychiatric sequelae (APNS) remain poorly understood. Here, we characterized longitudinal molecular changes among trauma survivors across ten APNS domains, including pain, anxiety, and depression. Recovery across these diverse clinical outcomes was associated with a shared, temporally coordinated transcriptional signature, characterized by early innate immune activation, subsequent homeostatic and wound-healing processes, and later adaptive immune responses. In contrast, chronic APNS trajectories exhibited limited transcriptional remodeling. We derived and externally validated an RNA-based Recovery Score (RRS) capturing the shared molecular response underlying recovery. Higher RRS was associated with greater clinical recovery, elevated peritraumatic cortisol, and lower cumulative stress exposure. Drug-response profiling identified candidate compounds predicted to mimic recovery-associated transcriptional changes. Together, these findings support posttraumatic recovery as an active biological process and identify shared molecular pathways that may be harnessed to prevent multiple adverse posttraumatic outcomes.