Cognitive protection of sinomenine in type 2 diabetes mellitus through regulating the EGF/Nrf2/HO‐1 signaling, the microbiota‐gut‐brain axis, and hippocampal neuron ferroptosis

Abstract Recent years have witnessed a growing research interest in traditional Chinese medicine as a neuroprotective nutrient in the management of diabetic cognitive dysfunction. However, the underlying molecular mechanisms of sinomenine in mediating ferroptosis of hippocampal neurons have been poorly understood. This study sought to decipher the potential effect and molecular mechanism of sinomenine in the cognitive dysfunction following type 2 diabetes mellitus (T2DM). Multi‐omics analysis was conducted to identify the microbiota‐gut‐brain axis in T2DM patient samples obtained from the publicly available database. In HT‐22 cells, erastin was utilized to create a ferroptosis model, and streptozotocin was injected intraperitoneally to create a rat model of DM. It was noted that intestinal flora imbalance occurred in patients with T2DM‐associated cognitive dysfunction. Sinomenine could reduce Erastin‐induced hippocampus neuronal ferroptosis by increasing EGF expression. EGF protected hippocampal neurons against ferroptosis by activating the Nrf2/HO‐1 signaling pathway. Furthermore, in vivo results confirmed that sinomenine blocked ferroptosis of hippocampal neurons and alleviated cognitive dysfunction in T2DM rats. Collectively, these results suggest that sinomenine confers neuroprotective effects by curtailing hippocampal neuron ferroptosis via the EGF/Nrf2/HO‐1 signaling and microbiota‐gut‐brain axis. It may be a candidate for the treatment of diabetic cognitive dysfunction.