2. Academic Validation
  3. High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy-lysosomal pathway in endometrial cancer

High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy-lysosomal pathway in endometrial cancer

  • Cell Death Dis. 2025 Mar 17;16(1):182. doi: 10.1038/s41419-025-07499-y.
Xiaodan Mao # 1 2 3,  Lixiang Huang # 1 3,  Xianhua Liu # 3 4,  Xite Lin # 1 2 3,  Qibin Wu 3,  Xinrui Wang 2 5,  Yuan Ren 1 3,  Jincheng Ma 1 3,  Maotong Zhang 1 2 3,  Yao Lin 6,  Damian J Ralser 7,  Alexander Mustea 7,  Gang Chen 8,  Pengming Sun 9 10 11
Affiliations

Affiliations

  • 1 Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China.
  • 2 Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China.
  • 3 Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China.
  • 4 Pathology Department, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China.
  • 5 Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350013, China.
  • 6 Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China.
  • 7 Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
  • 8 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 9 Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China. fmsun1975@fjmu.edu.cn.
  • 10 Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China. fmsun1975@fjmu.edu.cn.
  • 11 Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China. fmsun1975@fjmu.edu.cn.
  • # Contributed equally.
PMID: 40097416 DOI: 10.1038/s41419-025-07499-y
Abstract

Endometrial Cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and Apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA Sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting Enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769HK2 vs. ARG 313HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC Organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and Cholesterol metabolism.

Figures
Products