Abstract

Endometriosis (EMs) is a disease characterized by the presence of endometrial tissue outside the uterus, which often causes pain, abnormal bleeding, and infertility. Sirtuin 1 (SIRT1)-mediated deacetylation is implicated in the progression of various diseases, yet its role in EMs remains unexplored. Normal, ectopic, and eutopic endometrial tissues from EMs or non-EMs patients were collected. RT-qPCR and Western blot analyses were performed to evaluate SIRT1 expression. Cell viability, migration, and invasion of human endometrial stromal cells (HESCs) were assessed using the MTT assay, Transwell migration, and invasion assays. Protein levels were analyzed via Western blot. The interaction between SIRT1 and high mobility group box 1 (HMGB1) was examined using co-immunoprecipitation. Finally, an EMs rat model was developed. Results demonstrated that both eutopic and ectopic endometrial tissues exhibited elevated SIRT1 expression. Furthermore, SIRT1 deficiency suppressed HESC viability, migration, invasion, and a phenotypic shift, as well as autophagy. Mechanistically, SIRT1 deficiency reduced HMGB1 protein stability in HESCs. Additionally, HMGB1 overexpression enhanced HESC viability, migration, invasion, autophagy, and induced a phenotypic switch characterized by downregulation of mesenchymal markers (e.g., vimentin, N-cadherin) and upregulation of the epithelial marker E-cadherin. In the rat model, SIRT1 silencing suppressed this phenotypic switch and autophagy in uterine tissue. Collectively, SIRT1-mediated deacetylation of HMGB1 at lysine 12 stabilized HMGB1 protein, promoting autophagy and enhancing the invasive and migratory capacity of HESCs, thus driving EMs progression—offering novel therapeutic insights for EMs treatment.