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Summary-data-based Mendelian Randomization and colocalization analysis were employed to explore causal relationships between hypoglycemic drug targets and POF risk, integrating multi-omics data to uncover underlying genetic and metabolic mechanisms. A significant association was revealed between elevated dipeptidyl peptidase-IV (DPP4) expression levels and reduced POF risk. This association remained robust following multiple testing correction and colocalization analysis. In subsequent methylation level analysis, three CpG sites\u00a0in DPP4 were identified, where elevated methylation levels were associated with increased POF risk. Furthermore, increased DPP4 protein levels were demonstrated to be associated with reduced POF risk. Through the integration of multi-omics evidence and two-sample Mendelian randomization analysis, the findings were further validated, with sensitivity analyses confirming the stability of the results and the absence of significant pleiotropy or heterogeneity. It was demonstrated that increased DPP4 gene expression and protein levels have protective effects against POF, whereas elevated methylation at specific CpG sites is associated with increased POF risk. 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