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

## TL;DR

TRIM56 worsens brain injury after blood flow is restored by reducing protective signals, suggesting it could be a target for new treatments.

## Contribution

TRIM56's role in promoting neuronal ferroptosis via KLF4 degradation is newly identified as a potential therapeutic target for cerebral I/R injury.

## Key findings

- TRIM56 knockout mice show reduced neurological deficits and inflammation after I/R injury.
- TRIM56 promotes ferroptosis by ubiquitinating and degrading KLF4, suppressing the xCT/GSH/GPX4 axis.
- Farudodstat, a TRIM56 inhibitor, reduces I/R injury in both in vitro and in vivo models.

## 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.

This study reveals that the E3 ubiquitin ligase TRIM56 exacerbates neuronal ferroptosis and brain damage by mediating K48‐linked ubiquitination and degradation of KLF4, leading to suppression of the xCT/GSH/GPX4 axis. Targeting TRIM56 alleviates cerebral ischemia‐reperfusion injury in vivo and in vitro, highlighting its therapeutic potential.