Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic imbalance, oxidative stress, and granulosa cell (GC) dysfunction. Given the established role of BRCA1 in maintaining genomic stability and regulating stress responses, its potential involvement in PCOS pathogenesis warrants investigation. We examined the impact of BRCA1 on PCOS using a dehydroepiandrosterone (DHEA)-induced mouse model and testosterone-stimulated KGN cells. Lentiviral vectors overexpressing BRCA1 were administered by ovarian injection in PCOS mice or used to infect KGN cells. The IL-1β, TNF-α, and IL-6 levels were measured using enzyme-linked immunosorbent assay. Western blotting was performed to evaluate the expression levels of BRCA1 and other proteins related to inflammation, apoptosis, and endoplasmic reticulum stress (ERS). A TUNEL assay and flow cytometry were used to assess cell apoptosis. Spectrophotometry was used to measure the levels of reactive oxygen species, malondialdehyde, superoxide dismutase, and catalase. Cell survival was evaluated using a CCK-8 assay. Hematoxylin and eosin staining was used to assess the pathological alterations in the ovaries of PCOS mice. Additionally, rescue experiments were conducted on KGN cells treated with the ERS inducer thapsigargin (TG) to determine whether the protective effects of BRCA1 overexpression could be reversed through reactivating ERS. BRCA1 expression was reduced in PCOS. BRCA1 overexpression normalized sex hormone levels, improved ovarian morphology, and attenuated inflammatory signaling, oxidative stress, apoptosis, and ERS in vivo and in vitro. Notably, the ERS inducer TG reversed these protective effects, indicating ERS dependence. These findings suggest that BRCA1 mitigates PCOS phenotypes primarily by suppressing ERS and downstream inflammatory/oxidative and apoptotic pathways, thereby highlighting BRCA1 as a potential molecular target for PCOS therapy.