Neurotoxic A1 astrocytes promote neuronal ferroptosis via CXCL10/CXCR3 axis in epilepsy

Epilepsy is a common neurological disorder with a complex etiology. Ferroptosis, a new form of programmed cell death, is characterized by the accumulation of lipid peroxides and associated with seizures. However, the underlying mechanism of ferroptosis in epilepsy remains elusive. Here, we found that GPX4-GSH-dependent neuronal ferroptosis was detected in epileptic mice, which was attenuated with ferroptosis inhibitors. Moreover, activated neurotoxic A1 astrocytes facilitated seizure-related neuronal ferroptosis in epileptic brains. Inhibition of ferroptosis blocked A1 astrocyte-induced neurotoxicity. A1 astrocyte-secreted CXCL10 enhanced STAT3 phosphorylation but suppressed SLC7A11 in neurons via CXCR3, leading to ferroptosis-associated lipid peroxidation in a GPX4-dependent manner. This was in line with clinical findings, showing a significant correlation between neuronal ferroptosis and A1 astrocytes in epileptic patients. In summary, the present data show that A1 astrocyte-induced neuronal ferroptosis contributes to the pathogenesis of epilepsy, which offers a novel therapeutic target for precision medicine.

Automated summary

Epilepsy is a common neurological disorder, and a new form of cell death called ferroptosis is associated with seizures. This study found that neuronal ferroptosis dependent on GPX4-GSH was detected in epileptic mice and could be attenuated by ferroptosis inhibitors. Additionally, neurotoxic A1 astrocytes activated in epilepsy facilitated seizure-related neuronal ferroptosis. Inhibiting ferroptosis blocked A1 astrocyte-induced neurotoxicity. A1 astrocyte-secreted CXCL10 enhanced STAT3 phosphorylation but suppressed SLC7A11 in neurons, leading to ferroptosis-associated lipid peroxidation in a GPX4-dependent manner. Clinical findings also showed a significant correlation between neuronal ferroptosis and A1 astrocytes in epileptic patients. In conclusion, this study reveals that A1 astrocyte-induced neuronal ferroptosis contributes to the pathogenesis of epilepsy, providing a novel therapeutic target for precision medicine.