The protective role of the G3BP1 - FTH1 axis within stress granules against ferroptosis during acute ischemic stroke injury.

Ferroptosis is a key mechanism leading to neural damage in acute ischemic stroke (AIS). The production of stress granules (SGs) has also been reported to regulate AIS injury. However, the intrinsic link between SG formation and ferroptosis remains poorly understood. This investigation examined the interaction between the SG core protein G3BP1 and ferritin heavy chain 1 (FTH1) in AIS and its role in controlling ferroptosis. Using models of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in cells, together with immunofluorescence, co-immunoprecipitation (Co-IP), and the detection of ferroptosis, we observed that SG formation was inversely correlated with ferroptotic injury during AIS. G3BP1 and FTH1 interact dynamically during AIS injury, and the extent of this interaction was positively correlated with FTH1 protein level and inversely with the severity of ferroptosis. Functional experiments further demonstrated that the deficiency of G3BP1 inhibits the formation of stress granules (SGs), exacerbates the down - regulation of FTH1, and enhances ferroptosis. In contrast, the overexpression of G3BP1 promotes the assembly of SGs, maintains the expression of FTH1, and consequently mitigates ferroptotic injury. The results of this study indicate that G3BP1 and stress granule formation are closely correlated with the maintenance of FTH1 protein levels, thereby mitigating ferroptotic damage in acute ischemic stroke (AIS). This finding provides new experimental evidence supporting a protective role for SG in ferroptosis, thereby presenting an innovative perspective and a potential therapeutic target for AIS.