SIRT6 mitigates oxidative stress and RSL3-induced ferroptosis in HTR-8/SVneo cells.

Dysregulation in placental trophoblast cells frequently results in oxidative stress, culminating in pregnancy-related complications. While iron is essential for fetal development, cellular ferroptosis due to elevated iron levels might mediate the emergence of preeclampsia (PE), presenting significant risks during gestation. We found abnormally activated oxidative stress and increased iron concentration in the placental tissues of PE patients. Subsequently, we treated placental trophoblasts with hydrogen peroxide and RSL3 to induce oxidative stress and ferroptosis models. The results revealed that SIRT6 overexpression activates the Nrf2/HO-1 pathway, restores the oxidative imbalance of the cells, and protects the cells from ferroptosis. Meanwhile, activation of the Nrf2/HO-1 pathway alone showed similar results. Thus, we posit that SIRT6, via the Nrf2/HO-1 pathway, alleviates cellular oxidative stress and diminishes ferroptosis, offering a novel therapeutic avenue for PE.