SMURF1 alleviates preeclampsia by suppressing ferroptosis in trophoblast cells via mediating ubiquitination of FLT1

Background Ferroptosis, an emerging form of regulated cell death, and ubiquitination have not been fully clarified in preeclampsia (PE). Aberrant overexpression of Fms-like tyrosine kinase 1 (FLT1) is closely associated with PE development, yet the association between FLT1 and ferroptosis in PE, as well as the involvement of ubiquitination in this process, remains unexplored.Methods To recapitulate PE pathophysiology, rat models were generated via N(G)-Nitro-L-arginine methyl ester (L-NAME) administration, and HTR-8/Svneo cells were subjected to hypoxic stress. The expression patterns of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) and FLT1, as well as their regulatory relationship in trophoblast ferroptosis, were examined. Furthermore, the molecular mechanism by which SMURF1 regulates FLT1 and ferroptosis in PE was clarified via FLT1 knockdown, SMURF1 overexpression, Ferrostatin-1 treatment, and rescue experiments.Results We successfully established a PE rat model through L-NAME administration, with marked ferroptosis activation in placental tissues. FLT1 was notably upregulated and positively correlated with Fe2+ levels. Knockdown of FLT1 markedly attenuated ferroptosis, improved placental pathological damage, pregnancy outcomes, and clinical manifestations of PE. In vitro, FLT1 was highly expressed in PE-stimulated trophoblasts, and silencing FLT1 inhibited ferroptosis with an effect similar to that of the ferroptosis inhibitor Ferrostatin-1. Bioinformatics prediction and experimental validation revealed that SMURF1, a downregulated E3 ubiquitin ligase in PE models, associates with FLT1 and promoted its ubiquitin-dependent degradation. Moreover, overexpression of SMURF1 suppressed ferroptosis in PE-stimulated trophoblasts, an effect that was reversed by FLT1 restoration.Conclusions Downregulated SMURF1 in PE degrades FLT1 through ubiquitination, thereby suppressing ferroptosis in trophoblast cells, and alleviating placental pathological injury and PE-related symptoms. This study reveals the central regulatory function of the SMURF1-FLT1-ferroptosis pathway in PE progression, providing fresh perspectives on the link between placental damage and ferroptosis.