Abstract
Cognitive impairment remains one of the most prevalent and debilitating sequelae of traumatic brain injury (TBI), profoundly compromising long-term quality of life. Nevertheless, effective treatment options are limited, as the complexity of post-TBI pathology often exceeds the protective scope of conventional neuroprotective strategies. Accumulating research has revealed regulated cell death (RCD) as a central driver of neuronal loss and cognitive decline post-TBI. Consequently, targeting RCD pathways has emerged as a promising strategic direction for alleviating post-TBI cognitive impairment. This review provides an analysis of the molecular mechanisms underlying five major RCD forms, including apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, it critically assesses the therapeutic potential of these pathways while examining their complex interplay in post-TBI cognitive impairment. By systematically synthesizing recent advances in targeted therapeutic strategies, we highlight that targeting RCD pathways paves the way for highly effective and precise therapeutic modalities against post-TBI cognitive impairment, although challenges in multi-target combination therapies and brain delivery warrant further investigation.