Hypericin alleviates high glucose-induced ferroptosis in cultured rat satellite glial cells via targeting P2X7R to activate the Akt/GSK3β/Nrf2 axis.

Hyperglycemia is a major risk factor for diabetic cardiovascular autonomic neuropathy (DCAN), but the underlying cellular mechanisms remain incompletely understood. To address this gap, this in vitro study aimed to determine whether high glucose induces ferroptosis in primary satellite glial cells (SGCs) isolated from rat stellate ganglia (SG) and to evaluate the protective mechanism of hypericin. Our results showed that high glucose markedly upregulates P2X7 receptor (P2X7R) expression in SGCs, leading to reduced cell viability and characteristic ferroptotic events, including increased levels of reactive oxygen species (ROS), abnormal iron accumulation, enhanced lipid peroxidation, and a marked decline in both glutathione (GSH) content and the activity of glutathione peroxidase 4 (GPX4). Hypericin at 0.1 μmol/L exhibited strong protective effects against high glucose-induced injury. Mechanistically, hypericin directly binds to the K110 site of P2X7R, inhibiting its function and subsequently activating the Akt/GSK3β pathway. This activation stabilizes Nrf2 by suppressing its ubiquitin-mediated degradation, promotes Nrf2 nuclear translocation, and upregulates the GPX4/SLC7A11 antioxidant axis. Genetic knockdown of P2X7R or Nrf2 confirmed their essential roles in this pathway. These findings reveal a previously unrecognized mechanism by which hypericin alleviates SGCs ferroptosis under high glucose conditions through the P2X7R/Akt/GSK3β/Nrf2 axis, highlighting its potential relevance to DCAN.