It was found that icariin could directly regulate glucose-regulated protein 78 (GRP78), inositol requiring enzyme-1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) to inhibit endoplasmic reticulum (ER) stress and repress the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1s) pathway, reduce microglial activation in the ischemic penumbra, decrease the expression and release of proteins such as IL-1β and TNF-α to exert anti-inflammatory effects to attenuate ischemic stroke injury (Zheng et al., 2022; Mo et al., 2021; Tao et al., 2024). Here, ERN1 is linked to ischemic stroke.