2. Academic Validation
  3. Excess heme orchestrates progesterone resistance in uterine endometrial cancer through macrophage polarization and the IL-33/PAX8/PGR axis

Excess heme orchestrates progesterone resistance in uterine endometrial cancer through macrophage polarization and the IL-33/PAX8/PGR axis

  • Biomed Pharmacother. 2025 May:186:118008. doi: 10.1016/j.biopha.2025.118008.
Jia-Jing Lu 1,  Yan Ning 2,  Wen-Ting Hu 3,  Yan-Ran Sheng 3,  Yu-Kai Liu 3,  Feng Xie 4,  Ming-Qing Li 5,  Xiao-Yong Zhu 6
Affiliations

Affiliations

  • 1 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, PR China; Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, PR China.
  • 2 Department of Pathology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, PR China.
  • 3 Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, PR China.
  • 4 Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, PR China.
  • 5 Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, PR China; Department of Reproductive Immunology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China. Electronic address: mqli@sjtu.edu.cn.
  • 6 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, PR China; Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, PR China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, PR China. Electronic address: zhuxiaoyong@fudan.edu.cn.
PMID: 40138919 DOI: 10.1016/j.biopha.2025.118008
Abstract

Progesterone is an important drug for hormone therapy in uterine endometrial Cancer (UEC). However, the therapeutic efficacy of progestogen is often limited by resistance, and the underlying mechanism remains unknown. In this study, we observed heme metabolism is more active in progesterone-insensitive patients. Heme induced macrophages (Mφs) bias towards M2-like phenotype and downregulated the expression of IL-33, resulting in increased levels of Paired box gene 8 (PAX8). Further study showed PAX8 inhibited the transcriptional activity of PGR by binding to the PGR promoter region. In addition, PGR can also act as a transcriptional factor to regulate the transcription of autophagy-related gene 7 (ATG). Low expression of PGR decreases the transcriptional activity of Atg7 promoter, which decreases cell Autophagy and promotes the progression of UEC. Overall, this study reveals the important interaction between heme metabolism, IL-33 and PGR in progesterone-insensitive UEC, and is promising to provide new therapeutic targets for overcoming progesterone resistance.

Keywords

Autophagy; Heme; Interleukin 33; Progesterone receptor; Uterine endometrial cancer.

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