Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Uterine fibroids involve abnormal cell proliferation and fibrosis, with epithelial-mesenchymal transition (EMT) playing a key role. Mitochondrial-endoplasmic reticulum stress and related signaling pathways are implicated in this process, but the potential of natural extracts for modulation remains underexplored. Objective: This study aimed to investigate whether Atractylodes macrocephala extract can reverse EMT progression in uterine fibroids by regulating mitochondrial-endoplasmic reticulum stress via relevant signaling pathways. Methods: A mouse model of uterine fibroids was established and divided into normal, model, and Atractylodes macrocephala extract groups. Measurements included uterine weight, organ coefficient, cell proliferation, and apoptosis rate. Caspase-4 activity analysis, Western blotting, and immunofluorescence microscopy were used to assess protein and gene expression related to EMT, apoptosis, and signaling pathways. Results: The uterine fibroid model was successfully established. Treatment with Atractylodes macrocephala extract significantly inhibited uterine fibroid cell proliferation, promoted apoptosis, and reduced fibrosis. Mechanistically, the extract ameliorated EMT by effectively suppressing PI3K/Akt pathway activity. It concurrently exacerbated endoplasmic reticulum stress (indicated by increased Caspase-4 activity) to promote apoptosis while enhancing lysosome generation. Conclusion: Atractylodes macrocephala extract inhibits proliferation, promotes apoptosis, and reduces fibrosis in uterine fibroids by suppressing the PI3K/Akt pathway and enhancing endoplasmic reticulum stress. These findings provide a novel strategic basis for developing natural targeted therapies against uterine fibroids.