Abstract

Ischemia–reperfusion injury (IRI) is an important determinant of tissue loss following restoration of blood flow in ischemic stroke, myocardial infarction, acute kidney injury, organ transplantation, hepatic surgery, intestinal ischemia, and pulmonary transplantation. Ferroptosis has emerged as a mechanistically important component of IRI because reperfusion simultaneously increases reactive oxygen species, redox-active iron, mitochondrial stress, and oxidation of polyunsaturated membrane phospholipids while weakening endogenous antioxidant defenses. Palm-derived tocotrienols are compelling candidates for intervention because their membrane-associated antioxidant chemistry is accompanied by effects on inflammation, mitochondrial function, lipid metabolism, and redox signaling. Recent experimental evidence further demonstrates that tocotrienols can directly suppress ferroptosis more effectively than corresponding tocopherols in pharmacological and genetic models. This qualitative literature review integrates contemporary evidence on ferroptosis across cerebral, myocardial, renal, hepatic, intestinal, and pulmonary IRI with current tocotrienol biology. The synthesis supports a dual- layer hypothesis whereby tocotrienols may directly terminate phospholipid radical propagation while indirectly strengthening cellular antiferroptotic resilience. Nevertheless, direct evidence involving standardized palm tocotrienol-rich fractions in organ-specific IRI remains limited, and human proof-of- mechanism studies are absent. Future work should differentiate tocotrienol isoforms, employ validated ferroptosis endpoints, define post-ischemic therapeutic windows, establish tissue pharmacokinetics, and test compatibility with contemporary reperfusion therapies.