Evodiamine attenuates neurological impairment by inducing PANoptosis in microglia after severe traumatic brain injury

Severe traumatic brain injury (sTBI) lacks effective therapies despite its high morbidity and mortality in young adults. Here, we demonstrate that evodiamine (EVO), a natural alkaloid from Evodia rutaecarpa, significantly improves neurological outcomes in a murine sTBI model (controlled cortical impact). EVO administration (0.3-3.0 mg/kg, intraperitoneal) attenuated cerebral edema, preserved neuronal ultrastructure, and reduced neuroinflammation by suppressing microglial activation and cytokine release. Mechanistically, while EVO showed no direct neuroprotection against H₂O₂, CoCl₂, or oxygen-glucose deprivation-injury in vitro, it significantly enhanced neuronal survival in BV2 microglia-OxyHb co-cultures. Crucially, EVO selectively induced PANoptosis - a coordinated activation of pyroptosis, apoptosis, and necroptosis with PANoptosome formation- in microglia, thereby disrupting their pro-inflammatory activity. This study identifies microglial PANoptosis as the primary therapeutic target of EVO to alleviate post-sTBI neuroinflammation. Our findings position EVO as a promising early-phase intervention for sTBI, offering the first evidence of microglial PANoptosis modulation in neurological therapeutics.