Targeting HSP90 as a therapeutic approach for endometriosis: insights from proteomic analysis

Endometriosis, a chronic inflammatory condition characterized by pain and infertility, remains a clinical challenge. Current hormonal and surgical treatments are often limited by side effects and high recurrence rates. In search of more effective and less invasive alternatives, we analyzed a single-cell RNA sequencing dataset of menstrual effluents from patients (GSE203191) and identified a significant upregulation of heat shock protein 90 (HSP90), suggesting its pathogenic involvement. Using primary endometrial stromal cells (ESCs) isolated from human ovarian endometrioma and a murine endometriosis model, we evaluated the therapeutic potential of HSP90 inhibition with 17-allylamino-17-demethoxygeldanamycin (17-AAG). In vitro, 17-AAG (10 nM-10 μM) reduced ESC viability and proliferation in a dose-dependent manner while increasing caspase-3 activity. In vivo, 17-AAG (30 μg/g) significantly attenuated ectopic lesion growth without impairing systemic parameters such as body weight, anti-Müllerian hormone, or estrogen levels. Proteomic profiling revealed disruption of HSP90 client networks, including downregulation of importin 4 and tubulin gamma complex protein 3, and upregulation of DnaJ heat shock protein family member B1, glutamate-ammonia ligase, and sequestosome 1. These findings highlight HSP90 as a promising non-hormonal therapeutic target in endometriosis, offering mechanistic insights and translational potential for more targeted, well-tolerated treatment strategies.