Hydroxysafflor yellow A inhibits neuronal ferroptosis and ferritinophagy in ischemic stroke

Abstract

Ischemic stroke is a significant cause of disability and mortality on a global scale, with neuronal dysfunction playing a critical role in its pathogenesis. Conventional treatment approaches for ischemic stroke involve surgical interventions and thrombolytic therapy, yet these methods frequently result in ischemia/reperfusion (I/R) injury. Recent studies have underscored the implication of diverse programmed cell death mechanisms, including ferroptosis, in the progression of ischemic stroke. Ferroptosis, a newly recognized form of cell death reliant on iron, is intricately linked to various neurological conditions. Despite the existing body of research on ferritinophagy and neuronal ferroptosis in the context of cerebral ischemia-reperfusion injury, there is a lack of understanding regarding the mechanisms involved in neuronal ferroptosis. This study seeks to explore the relationship between neuronal autophagy and neuronal ferroptosis using in vivo and in vitro models of cerebral ischemia/reperfusion. The findings of our study reveal a significant upregulation of the ferritinophagy-associated protein NCOA4 following cerebral ischemia/reperfusion, concomitant with the initiation of ferroptosis in neuronal cells. This observation offers compelling support for a direct association between neuronal ferritinophagy and ferroptosis. Hydroxysafflor Yellow A (HSYA), a traditional Chinese herb, shows promise in reducing brain ischemia/reperfusion injury, but its exact protective mechanism is still unknown. Our study reveals a new way HSYA protects the brain by preventing neuronal ferroptosis after a stroke, a mechanism not previously reported. In ischemia/reperfusion model, the activation of ferritinophagy can result in the degradation of ferritin, leading to an imbalance in iron homeostasis and ultimately inducing cell ferroptosis. HSYA has been shown to inhibit neuronal autophagy, thereby reducing ferritinophagy and protecting cells from undergoing ferroptosis • Our findings show a significant rise in the ferritinophagy-related protein NCOA4 after cerebral ischemia/reperfusion, aligning with the start of neuronal ferroptosis. • Our research strongly suggests a direct link between neuronal ferritinophagy and ferroptosis. • HSYA inhibits neuronal ferroptosis by blocking the ferritinophagy pathway post-ischemic stroke.

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