Realgar facilitates the Nrf2-Keap1-p62 positive feedback signaling axis via MAPKs and AKT to interfere with autophagy-induced apoptosis and oxidative stress in the hippocampus.

Realgar, as a commonly used traditional Chinese medicine, exerts both pharmacological and biological effects. However, the mechanism by which it causes nervous system injury remains unclear. This study aimed to elucidate the specific mechanism underlying the hippocampal neurotoxicity caused by realgar. Nrf2 is an important receptor of exogenous toxic substances and oxidative stress. We utilized a p38-specific inhibitor (SB20358), ERK1/2-specific inhibitor (PD98059), JNK-specific inhibitor (SP600125) and AKT-specific inhibitor (LY249002) to establish the corresponding animal models and explore how realgar activates Nrf2. We established an Nrf2-shRNA gene silencing model in rats and an autophagy-specific inhibitor treatment model to further explore realgar-induced neurotoxicity and the role of Nrf2 in realgar-induced damage to the hippocampus. The results showed that realgar passed through the blood-brain barrier and accumulated in brain tissue to induce central nervous system toxicity. The specific mechanism was that realgar activated MAPKs and AKT signaling molecules to activate the Nrf2-Keap1-p62 positive feedback signaling axis, induced abnormal autophagy initiation and degradation, and promoted oxidative damage and apoptosis in neurons. Effective measures should be taken to prevent and control the arsenic poisoning caused by realgar in the early stage, and this study provides a theoretical and practical basis for the rational use of drugs in the clinic.