Recurrent spontaneous abortion (RSA), characterized by three or more successive pregnancy losses before the 28th week of gestation with the same partner, affects 1–2 % of couples attempting conception (Bender Atik et al., 2023, Deng et al., 2022). While the etiology of approximately 50 % of RSA cases remains elusive, it is noteworthy that 80 % of these unexplained miscarriages are strongly associated with immunological factors (Abdollahi et al., 2015). Numerous treatment strategies exist for RSA stemming from diverse causes, targeting presumed risk factors for pregnancy loss (Deng et al., 2022). However, the efficacy of many of these medical interventions remains a topic of debate. Therefore, understanding the potential biological functions and molecular mechanisms underlying RSA is crucial for the development of innovative therapeutic targets.

Ferroptosis, a non-apoptotic form of cell death, is characterized as an iron-dependent regulated necrosis, triggered by extensive lipid peroxidation-induced membrane damage (Stockwell et al., 2017). Ferroptosis is a form of inflammatory cell death associated with the release of damage-associated molecular pattern signals or lipid oxidation products during tissue injury (Tang et al., 2021). Iron overload on the surface of endometrial cysts induces ferroptosis in endometrial stromal cells. This process hampers the secretion of the cytokine VEGFA, subsequently inhibiting endothelial cell angiogenesis via a paracrine pathway (Zhang et al., 2022). Endothelial cell ferroptosis directly impedes angiogenesis in placental tissues, consequently leading to miscarriage in pregnant mice (Zhang et al., 2023). Decidual stromal cells (DSCs), predominant within the maternal decidua during early pregnancy, play pivotal roles in embryo implantation and placentation (Du et al., 2021, Li et al., 2022a). These cells intricately participate in immune activities and regulation of decidual immune responses, thereby influencing the outcome of pregnancy (Shao et al., 2020). DSC ferroptosis can lead to RSA, indicating the potential regulatory effects of ferroptosis on immune activities in RSA (Sun et al., 2023). Consequently, targeting ferroptosis could be crucial in treating RSA. Nevertheless, the intricate relationship between ferroptosis regulators and RSA is yet to be fully elucidated.

This study systematically identified a prognostic signature associated with RSA, focusing on ferroptosis-related genes to elucidate its molecular mechanisms. We constructed and validated a diagnostic model, complemented by Mendelian randomization to ascertain the causal impacts of genetic variations on RSA. By classifying RSA patients into distinct subgroups and analyzing immune cell infiltration with prognostic genes, the research provides novel insights into the pathogenesis of RSA. The significance of this study lies in its identification of CISD2 as a pivotal gene in RSA, marking it as a potential ferroptosis-related therapeutic target.