From Coffee Alkaloid to Ovarian Targets: An Integrated Computational Framework for Trigonelline in Ovarian Aging.

Trigonelline, a coffee-derived alkaloid with antioxidant and mitochondrial effects, has been proposed as a candidate modulator of aging, but its specific role in ovarian aging remains unclear. In this study, we applied an integrated in silico strategy combining network pharmacology, protein-protein interaction analyses, molecular docking, 100-ns molecular dynamics simulations, and single-cell transcriptomic data to identify potential trigonelline targets relevant to ovarian aging. Among 57 predicted targets, five (MMP9, JAK2, PARP1, HDAC1, and CYP3A4) emerged as core candidates spanning extracellular matrix remodeling, genome and epigenome maintenance, and endocrine/xenobiotic metabolism. Structural and molecular dynamics simulations combined with single-cell expression patterns converged on PARP1 and MMP9 as the most plausible central mediators of trigonelline's putative age-modulating effects in the ovary, with JAK2 and HDAC1 as intermediate candidates and CYP3A4 as a likely systemic mediator. These exploratory findings provide a conceptual framework that links coffee-derived trigonelline to molecular pathways of ovarian aging and highlight specific targets and pathways for experimental validation in future nutrition and reproductive-aging studies.