Single-oocyte proteome-transcriptome co-profiling reveals a role of dysregulated lactate metabolism in oocyte aging

The declined oocyte quality with age is a major risk factor for female infertility. Although transcriptomic changes have been examined in aged oocytes, the proteomic landscape, which reflects the primary functional executors of genes, and factors shaping the landscape, remains largely unexplored. This gap limits our understanding of molecular features driving oocyte aging. To address this, we performed single-cell proteome/transcriptome co-profiling in GV and MII-aged oocytes from mice and humans, revealing species- and stage-specific proteomic/transcriptomic changes during oocyte aging. Strikingly, we observed uncoupled proteomic and transcriptomic alterations, indicating that proteomic changes in aged oocytes are not primarily driven by RNA alterations. Leveraging our single-cell profiling, we captured the molecular heterogeneity in aged oocytes and revealed MCT4 as a conserved oocyte aging biomarker. Functional studies suggested that MCT4 mediated oocyte aging via lactate export, and its inhibition improved aged oocyte quality. These findings indicated altered lactate metabolism as a driver and intervention target of oocyte aging and underscored the value of our profiling in dissecting oocyte aging.