European Journal of Pharmacology · Nov 2026
Functional contribution of TERT to mitigation of endometrial stromal cell senescence by metformin through modulation of the AKT/mTOR axis
By Lee W, Song G, Bae H
Uterine aging contributes significantly to infertility and adverse pregnancy outcomes, particularly in women of advanced reproductive age. While telomere dysfunction and cellular senescence are established hallmarks of aging, therapeutic strategies targeting these processes in the uterus remain limited. This study investigated the effects of metformin on senescence-associated phenotypes in hTERT-immortalized human endometrial stromal cells (THESCs) and examined the potential contribution of TERT and AKT/mTOR signaling. Through an integrative network pharmacology approach, we identified 37 overlapping targets related to metformin, senescence, and uterine function, with TERT, AKT, and mTOR emerging as key targets. Metformin significantly restored cell proliferation, reduced senescence markers (P16, P21), and alleviated mitochondrial dysfunction and oxidative stress in late-passage and D-galactose-treated THESCs. Notably, Metformin also increased relative telomere length and TERT expression. TERT knockdown attenuated selected metformin-associated effects, including changes in cellular phenotypes and AKT/mTOR signaling, supporting a functional contribution of TERT. Exploratory molecular docking identified predicted binding poses of metformin with TERT, AKT, and mTOR. Moreover, metformin treatment in aged mice was associated with improved uterine histological features and changes in TERT, AKT, mTOR, and P16 immunoreactivity, and an increased number of pups. Collectively, these findings support a functional contribution of TERT to selected metformin-associated responses in THESCs, accompanied by changes in mitochondrial and redox phenotypes and AKT/mTOR phosphorylation. Further studies are required to define the causal relationships among these pathways and determine their relevance to physiological reproductive aging.