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.