Chlorogenic acid attenuates endometrial senescence via mTOR modulation: A combined network pharmacology, in vitro, and in vivo study.

Advanced maternal age is correlated with increased infertility, often due to impaired decidualization and placentation. This study elucidated the senotherapeutic potential of chlorogenic acid (CGA), a phenylacrylate polyphenol as major compound of coffee, in endometrial stromal cells (ESCs). Using a passage number-induced senescence model, CGA reduced senescence markers (P16, P21), promoted proliferation, and upregulated decidualization markers (PRL, IGFBP1, FOXO1). In aged hTERT-immortalized ESCs, CGA enhanced mitochondrial biogenesis by upregulating mitochondrial complex genes and restoring mitochondrial function. Docking and molecular dynamics analyses demonstrated a high binding affinity of CGA toward mTOR (-8.29 kcal/mol), with stabilizing interactions at key residues. CGA treatment decreased mTOR expression in uterine tissue of aged mice in vivo. By modulating the mTOR/AMPK/SIRT1 pathway, CGA attenuates senescence and supports decidualization. These findings suggest CGA as a promising senotherapeutic candidate for improving endometrial function and addressing infertility related to advanced maternal age.