Emerging Therapeutic Targets and Signaling Networks in Ischemia–Reperfusion Injury

Ischemia-reperfusion injury remains a major challenge in modern regenerative medicine due to its complex mechanisms, lack of effective therapies, and persistent constrains to translating new interventions from bench to bedside. Currently, there are no FDA-approved drugs that directly target ischemia-reperfusion injury, highlighting a substantial therapeutic gap. While restoring blood flow is vital for salvaging ischemic tissue, the reperfusion process paradoxically triggers additional cellular damage. The clinical significance and complexity of ischemia-reperfusion injury underscore an urgent need for mechanistically targeted therapeutic approaches. Recent research has identified pivotal molecular targets-PHLDA1, SIRT6, PKM2, and ubiquitin-specific proteases (USPs)-that play key roles in modulating cellular responses such as oxidative stress, inflammation, metabolism, apoptosis, autophagy, ferroptosis, and blood-brain barrier dysfunction during ischemia reperfusion injury. Advances in understanding these mechanisms offer promising strategies for developing novel interventions to mitigate tissue damage and improve patient outcomes. This review critically examines these molecular targets, detailing recent advances and outlining future directions in ischemia reperfusion injury research.