Sci Transl Med. 2025 Oct;17(818):eadp0064. doi: 10.1126/scitranslmed.adp0064. Epub 2025 Oct 1.
ABSTRACT
Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine887 with alanine887 in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.
PMID:41032624 | DOI:10.1126/scitranslmed.adp0064
