Metformin inactivates the cGAS-STING pathway through autophagy and suppresses senescence in nucleus pulposus cells.

Abstract

Intervertebral disc degeneration (IVDD) is a complex process involving many factors, among which excessive senescence of nucleus pulposus cells is considered to be the main factor. Our previous study found that metformin can inhibit senescence in nucleus pulposus cells; however, the mechanism of such an action was still largely unknown. In the current study, we found that metformin inactivates the cGAS-STING pathway during oxidative stress. Furthermore, knockdown of STING (also known as STING1) suppresses senescence, indicating that metformin might exert its effect through the cGAS-STING pathway. Damaged DNA is a major inducer of the activation of the cGAS-STING pathway. Mechanistically, our study showed that DNA damage was reduced during metformin treatment; however, suppression of autophagy by 3-methyladenine (3-MA) treatment compromised the effect of metformin on DNA damage. In vivo studies also showed that 3-MA might diminish the therapeutic effect of metformin on IVDD. Taken together, our results reveal that metformin may suppress senescence via inactivating the cGAS-STING pathway through autophagy, implying a new application for metformin in cGAS-STING pathway-related diseases.

• Authors: Chenghao Ren, Jie Jin, Chenchao Li, Jianwei Xiang, Yaosen Wu, Yifei Zhou, Liaojun Sun, Xiaolei Zhang, Naifeng Tian
• Journal: Journal of cell science (J Cell Sci) Vol. 135 Issue 15 (08 01 2022) ISSN: 1477-9137 [Electronic] England
• PMID: 35722742 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. Published by The Company of Biologists Ltd.

Chemical References

• Membrane Proteins
• STING1 protein, human
• Metformin
• Nucleotidyltransferases
• cGAS protein, human

Topics

• Autophagy (physiology)
• Cellular Senescence (physiology)
• Humans
• Intervertebral Disc Degeneration (drug therapy, genetics, metabolism)
• Membrane Proteins
• Metformin (metabolism, pharmacology, therapeutic use)
• Nucleotidyltransferases (genetics, metabolism)
• Nucleus Pulposus (metabolism)