SETD7 regulates decidual senescence through FOXO1-dependent mechanisms in human endometrial stromal cells

Recurrent implantation failure (RIF) constitutes a significant challenge in reproductive medicine, with compromised endometrial receptivity identified as a principal etiological factor. Cellular senescence, characterized by irreversible cell cycle arrest and senescence-associated secretory phenotype (SASP), has been implicated in endometrial dysfunction. This investigation aims to elucidate the molecular mechanisms by which SETD7, a lysine-specific methyltransferase, regulates endometrial stromal cell senescence and decidualization processes.

Transcriptomic analyses from endometrial tissues on RIF patients were to evaluate SETD7 expression and its association with senescence-related and decidualization markers. In vitro experiments using human endometrial stromal cells (hESCs) assessed the effects of SETD7 upregulation on cellular senescence, decidualization capacity, and the expression of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Molecular pathway analyses were conducted to investigate SETD7-mediated regulation of the AKT-FOXO1 signaling axis. Pharmacological inhibition of FOXO1 phosphorylation was applied to determine its impact on restoring decidualization in RIF-derived hESCs. Clinical correlation analyses validated the relationship between SETD7 and FOXO1 expression in endometrial samples.

SETD7 expression was significantly upregulated in RIF endometria compared with fertile controls; this correlated positively with senescence-associated genes and inversely with decidualization markers. In vitro, SETD7 overexpression in hESCs induced senescence in a dose-dependent manner, increased expression of senescence markers, and severely suppressed PRL and IGFBP1 induction during decidualization. Mechanistically, SETD7 enhanced AKT-dependent phosphorylation of FOXO1 at T24, promoting FOXO1 protein accumulation. Pharmacological inhibition of FOXO1 phosphorylation attenuated senescence effects and partially restored decidualization capacity in RIF-derived hESCs. Clinical tissue analyses confirmed a strong positive correlation between SETD7 and FOXO1 expression.

These findings collectively establish SETD7 as a crucial molecular regulator of decidual senescence and identify it as a potential therapeutic target for enhancing endometrial receptivity in patients with recurrent implantation failure.