Traumatic brain injury (TBI) poses a significant global health challenge, where secondary injury processes driven by oxidative stress and metabolic crisis are key determinants of poor neurological outcomes, yet lack effective treatments. This review synthesizes emerging evidence on a novel neuroprotective pathway—the thioredoxin-1 (Trx1)–ataxia-telangiectasia mutated (ATM)–pentose phosphate pathway (PPP) axis. We elaborate on how this axis functions as an integrated redox-metabolic response system: oxidative stress triggers Trx1-dependent activation of ATM, which subsequently enhances PPP flux to boost NADPH production. This cycle creates a feed-forward loop that reinforces cellular antioxidant defenses, sustains redox homeostasis, and promotes neuronal survival. Preclinical findings demonstrate that bolstering this axis mitigates oxidative damage and improves recovery after TBI. Consequently, the Trx1-ATM-PPP axis presents a paradigm-shifting therapeutic target, moving beyond direct antioxidant scavenging towards modulating endogenous resilience networks. Future efforts to develop specific modulators of this pathway hold promise for pioneering new treatments for TBI and other CNS disorders linked to oxidative stress.

Traumatic brain injury, Oxidative stress, Redox regulation, Thioredoxin-1, ATM kinase, Pentose phosphate pathway