ANXA1 inhibits trophoblast ferroptosis in preeclampsia by downregulating KISS1†.

Abstract

Preeclampsia (PE) is a serious hypertensive disorder of pregnancy, significantly affecting maternal and neonatal health worldwide. It remains a leading cause of morbidity and mortality. Recent studies suggest a potential link between ferroptosis and PE. Annexin A1 (ANXA1), an endogenous anti-inflammatory mediator, can be activated by glucocorticoids, ischemia-reperfusion, inflammation, or oxidative stress. Ac2-26, a synthetic peptide derived from the N-terminal 26 amino acids of ANXA1, retains its anti-inflammatory properties. However, the regulatory mechanisms of ANXA1 in PE are not fully understood. In this study, we first observed in creased ferroptosis and reduced ANXA1 expression in preeclamptic placentas. A PE-like mouse model further confirmed placental ferroptosis, which was ameliorated by Ac2-26 treatment, improving pregnancy outcomes. In vitro, Ac2-26 targeted ANXA1, alleviated RSL 3-induced trophoblast dysfunction, and inhibited lipid peroxidation. Mechanistically, we found that increased KISS1 expression is closely associated with ferroptosis and PE, and that ANXA1 (Ac2-26) suppresses KISS1 expression, thereby mitigating ferroptosis. In summary, our findings identify a novel mechanism in which elevated KISS1 promotes ferroptosis in PE, and this process is counteracted by ANXA1 (Ac2-26) via KISS1 downregulation. This discovery offers a promising therapeutic strategy targeting ferroptosis in PE.