Nicotinamide Riboside Improves Mitochondrial Function and Oocyte Maturation in Aged Mice: A Multitarget Mechanistic Study Using Network Pharmacology and Molecular Simulations

Mitochondrial dysfunction plays a critical role in ovarian aging and the associated decline in female fertility. Nicotinamide riboside (NR), a vitamin B3 derivative and dietary NAD + precursor, has shown antiaging potential, yet its molecular mechanisms in ovarian function are not fully understood. In this study, we investigated the effects of NR on oocyte maturation, mitochondrial membrane potential, and mitochondrial distribution in aged mice. Using network pharmacology and protein–protein interaction analyses, we identified 54 potential NR‐related targets involved in ovarian aging, with CASP3, PTGS2, PARP1, REN, and ACE highlighted as central hub genes. Molecular docking and 100‐nanosecond molecular dynamics simulations confirmed stable and energetically favorable binding between NR and these targets, particularly PTGS2 and ACE, suggesting strong regulatory potential. To further place these targets in a physiological context, we reanalyzed publicly available human ovarian single‐cell RNA sequencing data and observed age‐associated remodeling of ACE, REN, PTGS2, and PARP1 expression across granulosa, theca/stromal, and endothelial cell populations, supporting their relevance within the ovarian microenvironment. NR treatment significantly enhanced the maturation rate and mitochondrial function of aged oocytes, indicating its ability to restore mitochondrial health and modulate key aging‐related pathways. These findings provide mechanistic insights into NR’s protective role in reproductive aging and support its potential as a nutritional intervention to promote female reproductive longevity.