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

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.