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

ABSTRACT: The liver's pivotal role in systemic iron metabolism makes it particularly susceptible to ferroptosis. Annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein with immunomodulatory properties, is implicated in inflammatory diseases. However, whether ANXA1 participates in ferroptosis and preserves iron homeostasis remains unclear. In this study, we observed that ANXA1 levels were inversely correlated with the severity of liver injury in patients and mice. Myeloid-lineage ANXA1 deletion exacerbated hepatic injury, inflammatory responses, and lipid peroxidation following ischemia-reperfusion. Transcriptomics revealed ferroptosis pathway enrichment in ANXA1-deficient macrophages. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE347530 | GEO | 2026/09/18

REPOSITORIES: GEO

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