Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.