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Procyanidins (PCs), which are organic antioxidants, suppress oxidative stress, exhibit anti−apoptotic properties, and chelate metal ions. The potential defense mechanism of PCs against cerebral ischemia/reperfusion injury (CIRI) was investigated in this study. Pre−administration for 7 days of a PC enhanced nerve function and decreased cerebellar infarct volume in a mouse middle cerebral artery embolization paradigm. In addition, mitochondrial ferroptosis was enhanced, exhibited by mitochondrial shrinkage and roundness, increased membrane density, and reduced or absent ridges. The level of Fe2+ and lipid peroxidation that cause ferroptosis was significantly reduced by PC administration. According to the Western blot findings, PCs altered the expression of proteins associated with ferroptosis, promoting the expression of GPX4 and SLC7A11 while reducing the expression of TFR1, hence inhibiting ferroptosis. Moreover, the treatment of PCs markedly elevated the expression of HO−1 and Nuclear−Nrf2. The PCs’ ability to prevent ferroptosis due to CIRI was decreased by the Nrf2 inhibitor ML385. Our findings showed that the protective effect of PCs may be achieved via activation of the Nrf2/HO-1 pathway and inhibiting ferroptosis. This study provides a new perspective on the treatment of CIRI with PCs.

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The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post‐reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti‐inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.