Neutrophil extracellular traps promote neuronal ferroptosis through STING-mediated AMPK dysregulation after traumatic brain injury.

Neuronal ferroptosis exacerbates neurological dysfunction after traumatic brain injury (TBI), yet the upstream signals driving this process remain poorly defined. Here, we identify neutrophil extracellular traps (NETs) as critical mediators of post-TBI ferroptotic injury. In patients, NET accumulation closely accompanied markers of neuronal ferroptosis and correlated with neurological severity. In a mouse TBI model, genetic ablation of peptidylarginine deiminase 4 (PAD4) or enzymatic degradation of NET-derived DNA markedly attenuated neuronal lipid peroxidation, suppressed ferroptosis-associated neuronal injury, and improved functional outcomes. Mechanistically, NET-derived DNA activated neuronal stimulator of interferon genes (STING) signaling, leading to suppression of intrinsic antioxidant defenses and amplification of lipid peroxidation. Pharmacological inhibition of STING or activation of AMP-activated protein kinase (AMPK) signaling effectively counteracted NET-induced ferroptotic stress and preserved neuronal viability. Collectively, these findings establish NET-derived DNA as a key upstream regulator of neuronal ferroptosis after TBI and highlight neutrophil-driven oxidative stress as a promising therapeutic target for secondary brain injury.