Aberrant autophagy–senescence axis drives spontaneous abortion through HSPA6/FOXO1-mediated decidual stromal dysfunction

Abnormal senescence of decidual stromal cells (DSCs) is tightly linked to spontaneous abortion, yet the underlying mechanisms remain poorly defined. In this study, we found that DSC senescence was significantly increased in the decidual tissues of patients with recurrent spontaneous abortion (RSA) during the first trimester. Using both in vitro and in vivo models, we show that abnormally elevated branched-chain amino acids (BCAAs) reduce autophagic flux, leading to excessive DSC senescence, which mechanistically involves aberrant heat shock protein A6 (HSPA6) upregulation and subsequent downregulation of the transcription factor forkhead box O1 (FOXO1), thereby predisposing to adverse pregnancy outcomes. In vivo studies, intervention with leucine, a key BCAA, promoted uterine senescence and induced adverse pregnancy outcomes in mice. Conversely, restoring autophagy with rapamycin effectively suppressed excessive senescence at the maternal-fetal interface and significantly improved pregnancy outcomes under high-leucine conditions. Therefore, this study demonstrates that excessive senescence at the maternal-fetal interface resulting from impaired autophagic flux disrupts pregnancy maintenance via the HSPA6-FOXO1 signaling pathway. These findings highlight the roles of metabolic dysregulation and autophagy imbalance in miscarriage and provide a potential mechanistic basis for therapeutic strategies to prevent spontaneous abortion.