The role of the SIRT1/FOXO1 axis in regulating autophagy and inflammation in endometriosis

BACKGROUND: Endometriosis, a common chronic gynecological disorder, involves cellular autophagy and inflammatory processes in its pathogenesis. However, the specific regulatory mechanisms of autophagy and inflammation in endometriosis remain unknown. In this research, the molecular mechanisms driving the progression of endometriosis are investigated. Through a combination of in vivo and in vitro experiments, this study examines the levels of autophagy and inflammation, as well as the regulatory relationship between SIRT1/FOXO1 and these biological processes. METHODS: In the in vivo experiments, we successfully established a rat model of endometriosis. The experimental subjects were then divided into a sham-operated group and a model group. Eutopic endometria from the sham group and both eutopic endometria and ectopic lesions from the model group were collected for analysis. The levels of SIRT1, FOXO1, TLR4, NF-κB, and autophagy were assayed through Western blot, PCR, and immunofluorescence experiments. In in vitro experiments, human endometriotic 12Z cells were subjected to FOXO1 inhibition, FOXO1 activation, and SIRT1 suppression to explore the regulatory effect of SIRT1/FOXO1 on cell autophagy and its relationship with endometriosis pathogenesis. The levels of SIRT1, FOXO1, TLR4, NF-κB, and autophagy were assayed through Western blot, PCR, and immunofluorescence experiments. Migration assay, CCK-8 and Transwell assay were used to detect the migration, proliferation, and invasion ability of 12Z. RESULTS: The findings demonstrated that autophagy was markedly upregulated in endometriosis in in vivo experiments. Further analysis indicated that this might be due to the downregulation of SIRT1 levels and the activation of FOXO1. Furthermore, the TLR4-mediated inflammation was significantly enhanced. In vitro experiments further confirmed that autophagy and inflammatory levels in endometriosis cells can be robustly upregulated by activating FOXO1, thus improving their migration, proliferation, and invasion abilities. After SIRT1 suppression, we observed that low SIRT1 levels could increase autophagy by upregulating FOXO1, while activating the TLR4/NF-κB-mediated inflammation, significantly enhancing the implantation, proliferation, and invasion of endometrial cells at the ectopic sites. CONCLUSION: Based on the in vivo and in vitro results, we found that lower SIRT1 levels could promote the migration, proliferation, and invasion of endometriosis cells by modulating FOXO1 and activating cellular autophagy and the TLR4/NF-κB-mediated inflammation, ultimately accelerating disease progression. By focusing on the SIRT1/FOXO1 axis, this study provides new insights into the pathogenesis of endometriosis and identifies promising treatment targets for future treatment.