USP46 sensitizes BeWo trophoblasts to ferroptosis by stabilizing CIRBP

Preeclampsia is a type of pregnancy complication that manifests as hypertension and albuminuria, associated with improper development of blood vessels in the placenta. However, the precise cause of preeclampsia is not well defined. Ferroptosis is a type of cell death involving abnormal accumulation of iron and lipid reactive oxygen species (ROS) in cells. Accumulating evidence indicates that ferroptosis may contribute to preeclampsia development, but the underlying mechanism remains unclear. Several ubiquitin-specific proteases (USPs) have been reported to repress ferroptosis, but whether other USPs regulate ferroptosis and preeclampsia development remains elusive. Here we identified USP46 as a potent regulator of erastin-induced ferroptosis in BeWo trophoblasts, which serve as an in vitro model to study preeclampsia. We found that overexpression of USP46 promoted erastin-induced ferroptosis in BeWo cells, while knockdown of USP46 led to resistance to erastin-induced ferroptosis. This resistance could be reversed by excessive cold-inducible RNA-binding protein (CIRBP). Immunoprecipitation experiments showed that USP46 interacts with CIRBP to inhibit its ubiquitination. These findings suggest that USP46 sensitizes BeWo cells to ferroptosis by stabilizing CIRBP. Insight Box Preeclampsia is a severe pregnancy complication with an unknown pathogenesis. Studies have shown that several ubiquitin-specific proteases (USPs) can inhibit ferroptosis and affect the occurrence of preeclampsia. However, given the numerous genes in the USP family, it remains unclear whether other USPs regulate ferroptosis and the development of preeclampsia. In this study, we identified USP46 as a strong regulator of ferroptosis in BeWo cells. USP46 interacts with CIRBP to reduce its ubiquitination and stabilize its expression, thereby promoting ferroptosis. This study reveals the key role of USP46 in regulating ferroptosis and provides a new target for etiological research and treatment of preeclampsia.