Regulatory Interplay of p53, AMPK, and mTOR in Decidualization: Implications for Reproductive Competence and Cancer Biology.

Endometrial dysfunction—particularly impaired decidualization—has emerged as a critical barrier to successful pregnancy establishment. Recent investigations have demonstrated that physiological cellular senescence actively participates in the decidualization process, indicating that the precise induction of moderate senescence appears to be essential for embryo implantation and the maintenance of pregnancy. The molecular pathways governed by p53, AMPK, and mTOR serve as pivotal regulators of cellular differentiation, metabolic homeostasis, autophagy, and senescence, and their coordinated interplay is fundamental to sustaining reproductive competence. In this review, we delineate the distinct regulatory mechanisms of these signaling networks in endometrial versus cancer cells and synthesize their respective roles within the context of reproductive biology. A comprehensive literature search was performed using PubMed and Google Scholar, without temporal limitations. Moderate p53 activity facilitates appropriate decidualization, whereas both hyperactivity and hypoactivity of p53 may lead to implantation failure and preterm birth. To conceptualize this dynamic, we propose a tripartite model of p53 activity (Zones 1–3). AMPK contributes to metabolic homeostasis through the inhibition of mTOR signaling; conversely, hyperactivation of mTOR promotes cellular senescence and disrupts decidualization. While these pathways are constitutively and irreversibly reprogrammed in cancer, they remain reversibly and hormonally regulated in a temporally specific manner in the pregnant endometrium, underscoring the context-dependent versatility of these molecular mediators under physiological versus pathological conditions. These insights highlight the critical role of physiological cellular senescence in reproductive biology and elucidate how its dysregulation may contribute to infertility and pregnancy-related pathologies.