Lithium Exposure Causes Trophoblast Cuproptosis by Upregulating FOXO1/STEAP4 Axis in Unexplained Miscarriage

Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu⁺ ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.