TRIM56 Aggravates Cerebral Ischemia‐Reperfusion Injury via Inhibiting KLF4‐Activated Ferroptosis Signaling

Abstract Cerebral ischemia‐reperfusion (I/R) injury often causes significant neuronal damage, neurological deficits, and long‐term disability. This study investigates the role of tripartite motif‐protein 56 (TRIM56) in cerebral I/R injury and elucidates the underlying mechanisms. Here, a significant increase in TRIM56 expression in the human brain, mouse brain, and primary neurons after cerebral I/R injury is first detected. TRIM56 knockout mice exhibit reduced neurological deficits and a diminished inflammatory response, with TRIM56 overexpression intensifying these effects. Mechanistic investigations demonstrate that TRIM56 promotes neuronal ferroptosis by directly interacting with Krüppel‐like factor 4 (KLF4) and triggering its K48‐linked ubiquitination‐dependent degradation. Moreover, compound screening identifies farudodstat as a potential TRIM56 inhibitor to reduce I/R injury in vivo and in vitro. In conclusion, TRIM56 critically regulates neuronal damage during cerebral I/R injury, thereby presenting as a potential therapeutic target for reducing brain I/R injury. Novel therapeutic strategies inhibiting TRIM56 or its downstream signaling pathways may be developed to mitigate the devastating effects of I/R injury on neuronal survival and function.