Cadmium disrupts IL6ST/STAT3 signaling involving FBXO2 in decidualization: Environmental trigger of spontaneous...

Cadmium (Cd), as a widespread environmental pollutant, poses a persistent threat to reproductive health due to its biological half-life of 30 years and endocrine-disrupting properties. Epidemiological studies have associated Cd exposure with adverse pregnancy outcomes such as spontaneous abortion (SA), although the underlying molecular mechanisms are largely unexplored. Decidualization is a critical process for embryo implantation and the maintenance of pregnancy. Impaired decidualization directly leads to spontaneous abortion. In this study, multi-element quantification in decidual tissues demonstrated significantly higher Cd concentrations in SA patients compared to normal controls, suggesting local Cd accumulation as a potential contributor to decidual dysfunction. Based on proteomic analysis of uterine Cd-exposed mouse models, we identified downregulation of F-box protein FBXO2, a key regulator of ubiquitination, which was further validated in decidual tissues from SA patients. Utilizing in vitro Cd-exposed stromal cell models and in vivo Cd-induced SA mouse model, we demonstrated that FBXO2 expression increases progressively during decidualization, whereas Cd exposure downregulates FBXO2 and its downstream IL6ST/STAT3 signaling axis, concomitant with impaired decidualization. Notably, FBXO2 overexpression enhanced K63-linked ubiquitination of IL6ST concomitant with restoration of STAT3 signaling, thereby rescuing Cd-induced suppression of decidualization markers PRL, IGFBP1, and FOXO1. Taken together, the results of our study predict potential Cd-binding sites on the FBXO2 protein and demonstrate that Cd disrupts decidualization by suppressing FBXO2 and its downstream IL6ST/STAT3 signaling, ultimately contributing to pathogenesis of SA.