Ischemia-reperfusion injury (IRI) is a critical factor in kidney transplantation, contributing to delayed graft function, reduced function, and increased rejection risk. This review explores the mechanisms of IRI and potential therapeutic targets. IRI occurs when blood flow is temporarily interrupted and then restored, leading to cellular damage through various biological pathways, including transcriptional reprogramming, apoptosis, necrosis, immune responses, and endothelial dysfunction. Tubular cells primarily rely on fatty acid β-oxidation for energy, but during IRI, this process is disrupted, leading to metabolic changes and cellular damage. The innate and adaptive immune systems are activated to clear damaged tissue and repair, but excessive inflammation can worsen injury. The complement system also plays a role in IRI, with complement activation contributing to tissue damage and immune responses. Metabolic reprogramming during IRI involves changes in mitochondrial function and energy production, with impaired mitochondrial function leading to increased ROS production and cell death. Mitophagy, the process of removing damaged mitochondria, is crucial for cell survival during IRI. The PINK1-Parkin pathway is involved in mitophagy and helps reduce IRI. Additionally, ferroptosis, a form of cell death linked to iron accumulation and lipid peroxidation, can contribute to IRI. The immune response during IRI involves the activation of toll-like receptors (TLRs), which recognize damage-associated molecular patterns (DAMPs) and trigger inflammatory responses. TLR4 and TLR2 are particularly involved in IRI, with their activation leading to increased inflammation and tissue damage. Macrophages and dendritic cells play a role in the immune response, and their activation can exacerbate IRI. T-cell activation and the Th1 and Th17 responses are also involved in IRI, with Th17 cells contributing to inflammation and tissue damage. Regulatory T cells (Tregs) have a protective role in IRI by suppressing immune responses and promoting tissue repair. The complement system is activated during IRI, with complement components such as C3 and C5 playing a role in tissue damage and immune responses. Inhibiting the complement cascade, particularly C5, has shown potential in reducing IRI. Prevention and therapeutic strategies for IRI include targeting the complement system, modulating immune responses, and improving organ preservation techniques. Future research may focus on the role of the Wnt/β-catenin pathway and other molecular mechanisms in IRI. Overall, a combination of approaches targeting different aspects of IRI is needed to improve outcomes in kidney transplantation.Ischemia-reperfusion injury (IRI) is a critical factor in kidney transplantation, contributing to delayed graft function, reduced function, and increased rejection risk. This review explores the mechanisms of IRI and potential therapeutic targets. IRI occurs when blood flow is temporarily interrupted and then restored, leading to cellular damage through various biological pathways, including transcriptional reprogramming, apoptosis, necrosis, immune responses, and endothelial dysfunction. Tubular cells primarily rely on fatty acid β-oxidation for energy, but during IRI, this process is disrupted, leading to metabolic changes and cellular damage. The innate and adaptive immune systems are activated to clear damaged tissue and repair, but excessive inflammation can worsen injury. The complement system also plays a role in IRI, with complement activation contributing to tissue damage and immune responses. Metabolic reprogramming during IRI involves changes in mitochondrial function and energy production, with impaired mitochondrial function leading to increased ROS production and cell death. Mitophagy, the process of removing damaged mitochondria, is crucial for cell survival during IRI. The PINK1-Parkin pathway is involved in mitophagy and helps reduce IRI. Additionally, ferroptosis, a form of cell death linked to iron accumulation and lipid peroxidation, can contribute to IRI. The immune response during IRI involves the activation of toll-like receptors (TLRs), which recognize damage-associated molecular patterns (DAMPs) and trigger inflammatory responses. TLR4 and TLR2 are particularly involved in IRI, with their activation leading to increased inflammation and tissue damage. Macrophages and dendritic cells play a role in the immune response, and their activation can exacerbate IRI. T-cell activation and the Th1 and Th17 responses are also involved in IRI, with Th17 cells contributing to inflammation and tissue damage. Regulatory T cells (Tregs) have a protective role in IRI by suppressing immune responses and promoting tissue repair. The complement system is activated during IRI, with complement components such as C3 and C5 playing a role in tissue damage and immune responses. Inhibiting the complement cascade, particularly C5, has shown potential in reducing IRI. Prevention and therapeutic strategies for IRI include targeting the complement system, modulating immune responses, and improving organ preservation techniques. Future research may focus on the role of the Wnt/β-catenin pathway and other molecular mechanisms in IRI. Overall, a combination of approaches targeting different aspects of IRI is needed to improve outcomes in kidney transplantation.