Dynamic regulation and targeted interventions of macrophages in ischemia–reperfusion injury

• Macrophages are crucial in IRI progression and recovery. • Key mechanisms of macrophage death in IRI. • Macrophage-immune cell interactions shape inflammation and tissue repair in IRI. • Therapeutic strategies target macrophage polarization and extracellular traps. • Organ-specific macrophage roles in IRI affect the heart, kidneys, liver, and brain. • Nano-drug delivery systems are advancing therapies targeting macrophages in IRI. Ischemia-Reperfusion Injury (IRI) is a complex pathophysiological process characterized by oxidative stress and inflammatory responses during tissue reperfusion, leading to severe organ dysfunction. Macrophages, as key immune cells, play a pivotal role in the pathogenesis of IRI, exhibiting dynamic functions that influence both tissue damage and repair. Despite extensive research, the precise mechanisms underlying macrophage-mediated IRI remain incompletely understood, necessitating a comprehensive review to explore their multifaceted roles and potential therapeutic targets. Aim of Review: This review aims to elucidate the diverse roles of macrophages in IRI, focusing on their involvement in programmed cell death mechanisms, communication with other immune cells, and regulatory effects on key organs affected by IRI. The review also explores potential therapeutic strategies targeting macrophages to mitigate IRI-induced injury. Key Scientific Concepts of Review: This article reviews the multifaceted roles of macrophages in IRI and explores various modes of macrophage programmed cell death induced by IRI, including gasdermin D-mediated pyroptosis, lipid peroxidation-associated ferroptosis, PARP-1-mediated PAR-dependent cell death, PANoptosis regulated by the PANoptosome, and the formation of macrophage extracellular traps (METs) induced by both reactive oxygen species-dependent and −independent pathways. Additionally, it discusses intercellular communication between macrophages and other immune cells in IRI, focusing on the bidirectional regulatory effects between macrophages and neutrophils, as well as their synergistic role in resolving inflammation. Moreover, the regulatory mechanisms of macrophages in IRI affecting key organs, such as the brain, lung, heart, kidneys and liver, have been systematically summarized. Finally, innovative therapeutic strategies targeting macrophages, including precise approaches such as regulating cell polarization, inhibiting excessive METs formation, and utilizing nano-drug delivery systems, are thoroughly analyzed. This review provides a significant theoretical foundation for clinical translational research on IRI. Ischemia-Reperfusion Injury (IRI) refers to the functional and structural alterations that occur when blood flow is restored following a period of ischemia. IRI is not only a key factor in the pathological progression of many diseases but also contributes to delayed graft recovery. Although the role of IRI has been extensively studied in various organs, the precise mechanisms and pathways involved remain poorly understood and are highly contentious. Beyond ischemia, reperfusion itself can exacerbate tissue and organ damage, particularly through inflammatory processes. Under normal conditions, macrophages protect the body from infection and regulate tissue inflammation. During ischemia, macrophages are activated by diverse signals and initiate an inflammatory response by releasing oxygen species (ROS), pro-inflammatory cytokines, and chemokines. Upon reperfusion, macrophages accumulate at the injury site, where they exert a dual function. On the one hand, they exacerbate inflammation and oxidative stress by producing cytokines, thereby aggravating tissue damage and dysfunction [1,2]. On the other hand, they facilitate tissue repair and regeneration by clearing cellular debris, promoting angiogenesis, and releasing growth factors that support tissue healing [3,4]. Therefore, gaining a comprehensive understanding of the molecular mechanisms underlying macrophage-mediated tissue damage and repair during IRI, as well as developing targeted therapeutic strategies, is essential for the clinical prevention and treatment of IRI.