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

Meng X, Xin Meng, Huimin Liu, Liu H, Ma Y, Yiming Ma, Qi J, Jiaze Qi, Zhang L, Limei Zhang, Xinyu Yang, Yang X, Jingwei Chen, Chen J
Journal of translational medicine · 2026 · vol. 24(1) · doi:10.1186/s12967-026-08196-w · PMID:42121211 · PMC13340353 · W7160919945
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-07 ⓘ

This study found that lower SIRT1 levels promote endometriosis progression by increasing FOXO1, enhancing autophagy, and activating TLR4/NF-κB-mediated inflammation, which improves endometrial cell migration, proliferation, and invasion.

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This study investigated how the SIRT1/FOXO1 axis regulates autophagy and inflammation during endometriosis using a rat endometriosis model with sham and model groups, and human endometriotic 12Z cells with FOXO1 inhibition/activation and SIRT1 suppression. In vivo, autophagy was upregulated in endometriosis tissues and was associated with decreased SIRT1, increased FOXO1 activation, and enhanced TLR4-mediated NF-κB inflammation, while in vitro FOXO1 activation increased autophagy and inflammation alongside greater migration, proliferation, and invasion. When SIRT1 was suppressed, low SIRT1 increased autophagy via FOXO1 and activated TLR4/NF-κB inflammation, enhancing ectopic implantation, proliferation, and invasion. This paper is centrally about endometriosis — it specifically maps the SIRT1/FOXO1 axis to changes in autophagy and TLR4/NF-κB inflammation that drive endometriosis progression.

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Abstract

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.
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Abstract

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. Similar content being viewed by others

Acknowledgements

We appreciate the support by the National Natural Science Foundation of China (82474558 and 82074483). Funding This study received financial support from the National Natural Science Foundation of China through grants numbered 82474558 and 82074483. Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate All experiments complied with standards established by the Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH) and were approved by the Animal Experiment Ethics Committee of Hebei University of Traditional Chinese Medicine (Approval No.: DWLL2020031). Conflict of interest The authors have disclosed that there is no conflict of interest for this research. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic Supplementary Material Below is the link to the electronic supplementary material. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Meng, X., Liu, H., Ma, Y. et al. The role of the SIRT1/FOXO1 axis in regulating autophagy and inflammation in endometriosis. J Transl Med (2026). https://doi.org/10.1186/s12967-026-08196-w Received: Accepted: Published: DOI: https://doi.org/10.1186/s12967-026-08196-w

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Condition tags

endometriosis

MeSH descriptors

Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy Autophagy

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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