Cuproptosis, a newly discovered form of copper-driven regulated cell death, has been shown to be closely related to ovarian function. However, whether the oocyte dysfunction, decreased ovulation efficiency, and cumulus cell aging caused by copper overload or imbalance are associated with regulatory pathways related to cuproptosis remains unclear. In this study, the expression profiles of genes related to cuproptosis in cumulus cells were comprehensively analyzed through transcriptome sequencing and metabolome analysis, and key genes and pathways that affect oocyte maturation were identified in response to elesclomol and CuSO4 treatment. Transcriptome analysis of cumulus cells revealed the differential expression of genes involved in key biological processes, such as cellular senescence (AKT3, MORC3, RBL1, etc.), gap junctions (GJA1, GNAI1, GJB3, etc.), steroid biosynthesis (FDX1, HSD17B7, CYP1A1, etc.), and cell cycle regulation (CDK2, CCNB2, MAPK7, etc.). Metabolomic analysis revealed significant changes in the levels of malic acid, PS (18:3(10,12,15)-OH(9)/14:0), and PA (21:0/LTE4), among other compounds. Subsequent Smart-seq analysis of oocytes revealed that after cuproptosis was induced in cumulus cells, oocyte maturation was disrupted, which affected genes associated with cellular senescence (TGFB2, SIRT1, CHEK2, etc.), oocyte meiosis (FBXO5, CCNB3, PLK1, etc.), and DNA methylation (PPM1D, DNMT3B, KMT2A, etc.). These findings provide deeper theoretical support for the key genes and biological processes involved in cumulus cell regulation and oocyte maturation, further clarifying the regulatory mechanisms of cuproptosis in the field of reproduction.
Keywords: Aging; Cattle; Metabolic reprogramming; Mitochondria; Multiomics analysis.
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