The Potential Role of p16 in the Regulation of Endometrial Reproductive Function

Age-related endometrial senescence has been suggested to be associated with reduced endometrial receptivity and less favorable outcomes of assisted reproductive technology (ART). However, molecular studies of endometrial aging remain limited compared with those of the ovary and oocytes, and the underlying mechanisms are incompletely understood. This review summarizes current evidence on cell cycle regulators in the human endometrium, with particular emphasis on p16 (cyclin-dependent kinase inhibitor 2A (CDKN2A)), and discusses their potential associations with senescence, decidualization, the immune microenvironment, ART outcomes, and tumor-related biology. A literature search of PubMed was conducted to identify basic and clinical studies published through October 2025. Available data suggest that appropriate levels and spatial distribution of p16 expression may be associated with successful implantation and favorable pregnancy outcomes, although evidence remains limited. p16-positive cells may influence the local immune milieu by modulating recruitment of monocytes, macrophages, and other immune cells via senescence-associated secretory phenotype factors. Emerging findings further suggest that p16 may exert context-dependent effects that can be conceptualized in two phases: a functional phase potentially supporting decidualization and pregnancy maintenance, and a persistent senescent phase possibly associated with chronic inflammation, endometrial dysfunction, miscarriage, and infertility. Collectively, these observations raise the possibility that p16 acts not only as a senescence marker but also as a dynamic regulatory factor in the endometrium. Further mechanistic and clinical studies are needed to validate this proposed framework.