Inhibition of P2X7R by hypericin improves diabetic cardiac autonomic neuropathy through the proteasome- Nrf2 - GPX4 signaling axis.

Hypericin (HYP), a primary active compound derived from Hypericum perforatum has been studied in the context of diabetes. The purpose of this study is to observe whether HYP can improve diabetic cardiac autonomic neuropathy (DCAN) and its possible mechanism. The current findings suggest that multiple drivers of ferroptosis in DCAN converge on the antioxidant protein nuclear factor erythroid 2-related factor 2(Nrf2). Overactivated P2X7 receptor (P2X7R) increases Nrf2 degradation by increasing proteasome activity through calcium ion accumulation. This work showed that HYP inhibited P2X7R expression, leading to elevated Nrf2 levels, thereby counteracting ferroptosis. This inhibition improves abnormal changes in cardiac function during the pathological process of DCAN in diabetic rats, including heart rate (HR), blood pressure (BP), heart rate variability (HRV), and sympathetic nerve discharge (SND). In summary, HYP enhances Nrf2 protein levels by suppressing P2X7R expression, reducing calcium-induced proteasome activity, and inhibits ferroptosis and inflammation. Thus, HYP alleviated DCAN progression.