Spatial Transcriptomic Atlas Reveals that FOXO3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis implicated the FOXO signaling pathway in mitochondrial dysfunction. Consistently, FOXO3 phosphorylation was significantly reduced in POI ovarian tissues. Pharmacological inhibition of this aberrant FOXO3 activation in a triptolide-induced POI model using KGN cells partially restored mitochondrial morphology and function.

Suppressing FOXO3 phosphorylation in normal KGN cells was sufficient to induce mitochondrial dysfunction. Together, these findings demonstrate that FOXO3-mediated disruption of mitochondrial dynamics drives granulosa-cell senescence and contributes to ovarian failure in POI. By combining spatial transcriptomics with functional and mechanistic analyses, this study provides a spatially resolved framework for understanding ovarian aging and identifies FOXO3-regulated mitochondrial pathways as promising targets for diagnosis and therapeutic intervention in POI.