Annexin A1 preserves iron homeostasis to suppress ferroptosis in hepatic ischemia-reperfusion injury

We identified FTH1, a key iron homeostasis regulator, as a novel ANXA1 interactor. Mechanistically, ANXA1 recruits the deubiquitinase UCHL5 to stabilize FTH1 by blocking ubiquitin-mediated degradation, reducing ROS and lipid peroxidation to suppress ferroptosis. The ANXA1-derived peptide Ac2-26 mitigated I/R-induced liver injury via this pathway.

Collectively, our findings suggest ANXA1 as a suppressor of ferroptosis that stabilizes FTH1 by inhibiting its ubiquitin-proteasome system (UPS)-mediated degradation, an autophagy-independent route of ferritin turnover, thereby preserving iron homeostasis and mitigating liver ischemia-reperfusion injury, indicating that ANXA1, along with its bioactive peptide Ac2-26, as both a master regulator of tissue repair and a promising therapeutic and diagnostic candidate for perioperative liver injury.