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

Abnormal senescence of decidual stromal cells is tightly linked to spontaneous abortion, yet the underlying mechanisms remain poorly defined. In this study, we found that the senescence level of DSCs in the decidual tissues of patients with recurrent spontaneous abortion (RSA) significantly increased 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 the core transcription factor forkhead box O1 (FOXO1) downregulation, thereby predisposing to adverse pregnancy outcomes. Both in vitro and in vivo experiments demonstrated that the reduced macroautophagy/autophagy flux resulting from abnormally elevated branched-chain amino acids (BCAAs) leads to excessive DSC senescence. 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 autophagy flux, disrupts pregnancy maintenance via the HSPA6-FOXO1 signaling pathway. These findings highlight the role of metabolic disorders and autophagy imbalance in miscarriage, and offer potential therapeutic strategies for preventing spontaneous abortion.