ANXA1 Inhibits Trophoblast Ferroptosis in Preeclampsia by Downregulating KISS1

Abstract Preeclampsia (PE) is a significant hypertensive disorder associated with pregnancy, impacting the health of women and children globally. It stands as one of the primary contributors to elevated morbidity and mortality rates among pregnant individuals and neonates. Recent investigations indicate a significant potential association between ferroptosis and PE. Annexin A1 (ANXA1) serves as an endogenous inhibitor of inflammation, capable of being activated by glucocorticoids, ischemia-reperfusion events, inflammatory processes, or oxidative stress. Ac2-26 is a synthetic peptide derived from the N-terminal 26 amino acids of the ANXA1 protein and retains its anti-inflammatory properties. Nevertheless, the precise regulatory mechanisms underlying ANXA1's role in PE remain to be fully elucidated. In this study, we first revealed that the increase in ferroptosis in preeclamptic placentas is accompanied by a downregulation of ANXA1 expression. Next, we established a PE-like mouse model and confirmed the presence of ferroptosis in the placentas of these mice. Ac2-26 treatment reduced placental ferroptosis and improved adverse pregnancy outcomes. Additionally, we demonstrated that targeting ANXA1 (Ac2-26) alleviates RSL3-induced trophoblast dysfunction and inhibits its promotion of intracellular lipid peroxidation. Subsequent mechanistic investigations have demonstrated that the elevation of KISS1 levels is intricately associated with ferroptosis and PE, while ANXA1 (Ac2-26) serves to inhibit KISS1 expression, thereby ultimately mitigating ferroptosis. In summary, this study presents the novel finding that elevated levels of KISS1 during pregnancy promote ferroptosis, a process that is mitigated by ANXA1 (Ac2-26) through the downregulation of KISS1 expression, thereby alleviating PE. This discovery offers a promising therapeutic strategy targeting the ferroptosis signaling pathway in PE.