Shikonin improves cerebral ischemia-reperfusion injury by regulating astrocyte polarization through ERK1/2-SP1-SLC7A10

Ischemic stroke (IS) is a leading cause of disability and mortality worldwide. In response to cerebral ischemia, astrocytes exhibit dual roles, either protecting or damaging neurons depending on their phenotypic state. Shikonin, a natural naphthoquinone compound derived from the traditional Chinese medicinal herb Lithospermum erythrorhizon (commonly known as 'Zicao' in traditional Chinese medicine), has demonstrated neuroprotective effects in IS animal models. However, the precise mechanisms by which Shikonin mitigates cerebral ischemia-reperfusion injury (CIRI) remain incompletely understood. In this study, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in cultured astrocytes, and a middle cerebral artery occlusion/reperfusion (MCAO/R) model was developed in SD rats. Small molecule activators and RNA interference were employed to determine whether Shikonin activates the ERK1/2-SP1-SLC7A10 signaling pathway to regulate astrocyte phenotypic transformation, thereby alleviating CIRI. The results showed that Shikonin significantly reduced cerebral infarct volume and improved neurological function in MCAO/R rats, accompanied by a shift in astrocytes from a pro-inflammatory to an anti-inflammatory phenotype. Similar findings were observed in OGD/R-treated astrocytes. Furthermore, overexpression of SLC7A10 markedly enhanced the neuroprotective effect of Shikonin in the MCAO/R model. Mechanistic studies revealed that Shikonin modulates astrocyte phenotype by targeting protein tyrosine phosphatases (PTPs), which act as critical upstream regulators of the ERK1/2-SP1-SLC7A10 signaling axis. These findings provide new insights into the development of astrocyte-targeted therapies for IS and support the therapeutic potential of authentic Shikonin from Xinjiang.