Estrogen receptor (ESR) 1 promotes uterine leiomyoma cell proliferation by enhancing mitochondrial energy metabolism via Wnt/β-catenin pathway activation.

BACKGROUND: Hyperactive mitochondrial energy metabolism supports the rapid proliferation of uterine leiomyoma cells. Estrogen receptor (ESR)-1 is associated with mitochondrial functions and the Wnt/β-catenin pathway; however, its regulatory roles in this pathway remain unclear. Therefore, we aimed to assess whether ESR1 enhances mitochondrial energy metabolism and regulates ferroptosis by activating the Wnt/β-catenin pathway. METHODS: Using the GSE593 dataset from the Gene Expression Omnibus and GeneCards databases, we identified ESR1 as the key hub gene. ESR1 knockdown rat uterine leiomyoma cell model (ELT3) was constructed to evaluate the cell proliferation, ferroptosis, and mitochondrial function changes. Moreover, Wnt/β-catenin pathway activator 1, AG1 was used to verify the regulatory relationship between ESR1 and this pathway. RESULTS: Bioinformatics analysis identified 22 mitochondria-related differentially expressed genes. Among these, ESR1 exhibited the highest connectivity in the protein–protein interaction network (degree = 5). ESR1 was highly expressed in ELT3 cells. ESR1 knockdown significantly inhibited cell proliferation, induced ferroptosis (increased the Fe²⁺ and malondialdehyde levels and caused disappearance of mitochondrial cristae), and reduced the mitochondrial membrane potential and levels of key energy metabolism-related proteins. Mechanistically, ESR1 knockdown inhibited the Wnt/β-catenin pathway (downregulated the β-catenin and p-GSK-3β(Ser9)/GSK3β levels). However, AG1 reversed these effects, restoring cell proliferation and mitochondrial functions. CONCLUSIONS: Overall, ESR1 enhanced mitochondrial oxidative phosphorylation by activating the Wnt/β-catenin signaling pathway, driving uterine leiomyoma cell proliferation. However, our findings suggest that its knockdown induces ferroptosis in leiomyoma cells, revealing a new strategy to prevent uterine leiomyoma recurrence.