Astrocytic LCN2 drives neuronal dysfunction in epilepsy by suppressing tunnel nanotube-mediated mitochondrial...

Epileptic seizures disrupt brain homeostasis not only by directly challenging neuronal excitability but also by impairing the intricate astrocyte-neuron cross-talk essential for metabolic support. Herein, we identify a novel pathogenic axis and a compensatory rescue mechanism that are critically interlinked. Following seizures, astrocytes initiate a protective response by forming tunneling nanotubes (TNTs) to deliver functional mitochondria to stressed neurons, thereby restoring neuronal bioenergetics. Paradoxically, this endogenous rescue pathway is suppressed by a seizure-induced, astrocyte-specific signaling cascade: the upregulation of Lipocalin-2 (LCN2) activates the NLRP3 inflammasome, triggering Gasdermin D-mediated pyroptosis and concurrently impairing TNT function. Crucially, genetic or pharmacological disruption of the LCN2/NLRP3 axis yielded dual therapeutic benefits-it robustly suppressed astrocytic pyroptosis and, unexpectedly, potentiated TNT-mediated mitochondrial transfer, leading to significant improvements in neuronal mitochondrial function and overall neurological outcomes. Our findings redefine the role of reactive astrocytes in epilepsy, revealing a single pathway that simultaneously controls an inflammatory death process and an intercellular organelle rescue system. Targeting this axis presents a promising therapeutic strategy to concurrently mitigate neuroinflammation and boost intrinsic neuroprotective mechanisms for improving post-seizure recovery.