Title : Targeting GDF15 alleviates mitochondrial dysfunction and ferroptosis in cerebral ischemia-reperfusion injury
Abstract:
Growth Differentiation Factor 15 (GDF15) is a well-recognized neurotrophic and regulatory factor. Serum levels of GDF15 are an independent risk factor for stroke and an effective predictor of ischemic stroke outcomes. Currently, there is a lack of research on the mechanism of GDF15 in ischemic stroke. This experiment aims to elucidate the key role of GDF15 in cerebral ischemia. Compared with the control group, the expression of GDF15 increased in OGD/R PC12 cells and tMCAO rats. Exogenous GDF15 significantly improved the damage in OGD/R PC12 cells and tMCAO rats, and this protective effect was related to its antioxidant, anti-inflammatory and anti-ferroptosis properties. In vitro, knockdown of GDF15 by siRNA exacerbated cell damage. The mechanism was verified by transcriptomics, RT-qPCR, Western Blot and immunofluorescence techniques. Kevetrin (a p53 activator) and Pifithrin-α (a p53 inhibitor) were used to detect the key role of GDF15 in the antioxidant and anti-ferroptosis mechanism. The mechanism study showed that GDF15 has a regulatory relationship with p53 and NOX4. p53 can promote the expression of GDF15, and GDF15 can inhibit the nuclear translocation of p53 and reduce the expression of NOX4, thereby regulating mitochondrial electron transport chain (such as SDHB, UQCRC2, ATP5A) and ferroptosis (TF, GPX4, SLC7A11) related targets, reducing ROS production, alleviating oxidative stress damage, improving mitochondrial dysfunction and inhibiting neuronal cell ferroptosis. GDF15 plays an important role in ischemic stroke, and targeting GDF15 is a potential strategy for the treatment of ischemic stroke.
