The spatial architecture of ovarian aging is driven by Onecut2-mediated luteal remodeling

Ovarian aging involves stromal fibrosis and immune cell infiltration, but how molecular drivers are spatially organized across tissue compartments is unclear. We used 10x Xenium spatial transcriptomics combined with single-cell RNA sequencing to build an atlas of the aging mouse ovary, comparing young and aged tissues. We identified a previously uncharacterized cellular niche in the luteal that undergoes age-dependent remodeling, with altered neighborhood enrichments and disrupted ligand-receptor interactions pointing to impaired local communication. Gene regulatory network analysis revealed that the transcription factor Onecut2 is significantly downregulated in aged ovaries within this niche and implicates ovarian microenvironment via the regulation axis between luteal and granulosa cells. These results identify spatial and molecular mechanisms of ovarian aging and point to ONECUT2 as a potential therapeutic target for preserving reproductive function and extending fertility.