Targeting Neuroinflammation After Traumatic Brain Injury: Addressing Sex Differences to Improve Clinical Translation

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Following the initial mechanical insult, a complex secondary injury cascade is triggered, resulting in neuroinflammation that can exacerbate neuronal damage and contribute to long-term neurological and psychiatric complications. Despite the development of numerous promising therapies targeting neuroinflammation after TBI, none have successfully translated from preclinical research into clinical practice. This persistent translational gap reflects limitations in preclinical and clinical study design, including inadequate representation of the biological heterogeneity of clinical TBI populations. This review critically evaluates the current landscape of therapies modulating neuroinflammatory pathways following TBI, with particular focus on how biological sex can influence therapeutic efficacy. Across multiple preclinical studies, sex-dependent differences were identified in molecular, histological, and functional responses to therapies targeting central regulators of neuroinflammation, indicating that biological sex can influence therapeutic efficacy across multiple inflammatory pathways. The influence of biological sex may also extend beyond preclinical development into clinical trials, where the underrepresentation of females and the failure to incorporate preclinical evidence of sex-dependent pharmacokinetics and therapeutic responses may represent potential contributors to variable or unsuccessful outcomes. Collectively, the evidence reviewed here suggests that biological sex may represent an important, yet underappreciated, contributor to the challenges of therapeutic translation and may obscure clinically meaningful treatment effects in defined patient subgroups. The findings presented throughout this review therefore suggest that biological sex should be considered a core component of therapeutic development, rather than solely as a secondary exploratory variable, to better characterise sex-dependent treatment responses and aid the clinical translation of therapies targeting neuroinflammation after TBI.