YY1-glycolytic axis promotes high glucose-induced cancer stemness in endometrial cancer: A multi-omics guided therapeutic strategy

Abnormal glucose metabolism in patients with diabetes mellitus or hyperglycaemia is a key factor leading to poor prognosis of endometrial cancer (EC) and warrants further exploration of its underlying mechanisms. In this study, we employed an integrative multiomics approach, including proteomics, transcriptomics, nontargeted metabolomics and single-cell metabolomics, and revealed that high glucose promotes EC cell stemness, thereby promoting tumour progression and reducing the sensitivity of EC cells to cisplatin (platinum-Pt^II). Mechanistically, there is a significant association between enhanced stemness and increased glycolytic activity in EC cells, and the transcription factor YY1 was found to be a key regulator of PDK1, CD133, and CD44 under high-glucose conditions, with YY1 binding to their promoter regions. Inhibiting YY1 expression effectively attenuates the stem cell properties of tumour cells and increases their sensitivity to cisplatin. Furthermore, we developed ROS-responsive nanoparticles for the codelivery of C8-Pt^IV-COOH and YY1 siRNA (NP-Pt^IV/siYY1), which synergistically amplify antitumour effects and chemosensitivity in patient-derived xenograft (PDX)-bearing mice with diabetes. Taken together, our results demonstrated that YY1 is a promising therapeutic target for inhibiting EC stemness and overcoming chemoresistance, particularly under high-glucose conditions.