OBJECTIVE: To investigate the role and underlying mechanism of sigma-1 receptor (SigmaR1)/high mobility group A1 (HMGA1) in the pathogenesis of diminished ovarian reserve (DOR). DESIGN: In vitro cell experimental study. SETTING: The Reproductive Medical Center, People's Hospital of Zhengzhou University. SAMPLE: Serum, follicular fluid (FF), ovarian granulosa cells (GCs) and KGN cells. METHODS: Samples were collected from DOR patients. Endoplasmic reticulum (ER) stress was induced in the GCs using thapsigargin (TG). mRNA and protein levels were determined using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell apoptosis and viability were assessed using flow cytometry and cell counting kit-8. Protein colocalization was detected via immunofluorescence. Molecular interactions were validated using co-immunoprecipitation, luciferase reporter and chromatin immunoprecipitation assays. MAIN OUTCOME MEASURES: Cell viability, cell apoptosis, SigmaR1, HMGA1 and ER stress-associated mRNA levels. RESULTS: SigmaR1 expression decreased while HMGA1 expression increased in the serum, FF and GC samples of DOR patients and TG-treated GCs. TG induced ER stress and GC apoptosis
these effects were diminished by SigmaR1 overexpression or HMGA1 silencing. SigmaR1 expressed in the nuclear envelope forms a complex with gene repressor-specific protein 3 (SP3) and histone deacetylase (HDAC)1/2/3
however, TG reduced SigmaR1 in GCs and blocked the complex formation. HMGA1, a transcriptional target of SP3, was negatively modulated by the SigmaR1/SP3 complex. HMGA1 overexpression abolished the protective effect of SigmaR1 on TG-induced ER stress and GC apoptosis. CONCLUSION: SigmaR1 formed a SmigaR1/SP3/HDAC complex to inhibit HMGA1 transcription, alleviating ER stress and GC apoptosis and providing new therapeutic targets for DOR.