Ubiquitination-dependent regulation of ferroptosis in ischemic heart and brain

Ischemia-reperfusion (I/R) injury is a major cause of tissue damage after myocardial infarction and ischemic stroke. Ferroptosis is an iron-dependent form of regulated cell death (RCD) marked by phospholipid peroxidation, and it is an important contributor to I/R-related injury. Although oxidative stress and lipid peroxidation are common features of I/R injury, they do not fully explain why ferroptosis sensitivity increases during reperfusion. Recent studies have shown that ferroptosis is also influenced by the ubiquitin system. Changes in ubiquitination and deubiquitination regulate key proteins involved in iron metabolism, lipid remodeling, and antioxidant defense, thereby altering cell susceptibility to ferroptosis under I/R stress. This review summarizes current evidence showing how ubiquitin-dependent regulation controls ferroptosis in both cardiac and cerebral I/R injury. We focus on mechanisms that disrupt iron homeostasis, weaken antioxidant defenses, increase oxidation-sensitive membrane lipids, and alter organelle stress responses. We also highlight the shared mechanisms in the heart and brain, while noting that the main ubiquitin-regulated control points differ between these tissues. In addition, we discuss emerging therapeutic strategies targeting selected E3 ubiquitin ligases and deubiquitinating enzymes. A better understanding of the ubiquitin-ferroptosis axis may support the development of more precise therapies for ischemic injury in the cardiovascular and cerebrovascular systems.