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

The age-related decline in oocyte quality is a major risk factor for female infertility. Although transcriptome has been examined in aged oocytes, proteomic landscape, which reflects primary gene functional executors, remains largely unexplored. This gap limits our understanding of oocyte aging. To address this, we perform single-cell proteome/transcriptome co-profiling of GV/MII-aged oocytes from mice and humans, revealing species- and stage-specific proteomic/transcriptomic changes during oocyte aging. Strikingly, we observe uncoupled proteomic and transcriptomic alterations, indicating that proteomic changes in aged oocytes are not primarily driven by RNA levels. Furthermore, we capture molecular heterogeneity in aged oocytes and identify MCT4 as a candidate marker of oocyte aging. Functional studies suggest MCT4 contributes to aging-associated oocyte defects via lactate export, and its inhibition improves aged-oocyte quality. These findings indicate altered lactate metabolism as a candidate marker and intervention target for oocyte aging and underscore the value of our profiling in dissecting oocyte aging. Age-related deterioration in oocyte quality is a key contributor to female infertility. Here, Cao et al. co-profile RNA and proteins in single mouse and human oocytes, revealing the molecular landscape and heterogeneity of oocyte aging and identifying MCT4-mediated lactate export as a potential marker and intervention target.