Dual Roles of Autophagy in Endometrial Fibrosis and Its Implications in Age-Related Reproductive Dysfunction.

Abstract

With the increasing prevalence of pregnancies at advanced maternal age, elucidating the molecular mechanisms underlying reproductive aging has become an important clinical challenge. In addition to ovarian aging, accumulating evidence suggests that age-related alterations in the endometrium contribute to impaired implantation and adverse reproductive outcomes. Autophagy, a highly conserved intracellular quality-control system, regulates mitochondrial homeostasis, metabolism, inflammation, and tissue remodeling. This review summarizes current evidence regarding the role of autophagy in endometrial fibrosis associated with reproductive aging. We first outline the general molecular mechanisms of autophagy-mediated fibrosis based on studies in multiple organs and then critically evaluate evidence specific to the endometrium. Impaired autophagy promotes oxidative stress, mitochondrial dysfunction, cellular senescence, epithelial-mesenchymal transition, fibroblast-to-myofibroblast transition, and extracellular matrix accumulation, thereby contributing to fibrotic remodeling and reduced endometrial receptivity. Conversely, under specific cellular and microenvironmental conditions, autophagy may facilitate profibrotic remodeling, highlighting its context-dependent dual role. We further discuss current evidence, limitations, and future research priorities, emphasizing the distinction between mechanisms established in the endometrium and concepts extrapolated from other organs. A better understanding of cell type-specific and age-dependent autophagy may facilitate the development of biomarkers and safe therapeutic strategies for endometrial fibrosis and reproductive aging.