The pathogenesis and treatment strategies of lower extremity ischemia–reperfusion injury

Lower extremity ischemia–reperfusion injury (LLIRI) refers to a cascade of pathological reactions initiated in tissues following the restoration of blood flow, which paradoxically exacerbates cellular damage. This article systematically reviews the core nuclear mechanisms underlying this process. During ischemia, the activation of anaerobic glycolysis and the accumulation of succinate within mitochondria lead to the abnormal buildup of acidic metabolites. Upon reperfusion, this is followed by a massive burst of reactive oxygen species (ROS), which directly induces oxidative damage to lipids, proteins, and DNA. Concurrently, ROS acts as a signaling molecule to activate pathways, such as nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK), thereby triggering a robust inflammatory response. This response is characterized by neutrophil infiltration, cellular damage, ion efflux, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated cellular pyroptosis. These pathological events synergize with calcium overload to induce mitochondrial permeability transition, leading to the opening of the mitochondrial permeability transition pore (mPTP). Ultimately, this process activates multiple programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis, resulting in irreversible tissue damage. In addition, this article discusses therapeutic strategies targeting the aforementioned mechanisms, including pharmacological interventions, such as antioxidants, anti-inflammatory agents, and specific inhibitors of cell death pathways, and non-pharmacological approaches, such as ischemic preconditioning, postconditioning, and hypothermia. Collectively, this review aims to provide theoretical support for the development of effective clinical strategies to alleviate lower extremity ischemia–reperfusion injury.