Reduced NRF2/Mfn2 activity promotes endoplasmic reticulum stress and senescence in adipose-derived mesenchymal stem cells in hypertrophic obese mice

doi:10.4252/wjsc.v17.i6.104367

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World Journal of Stem Cells

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World J Stem Cells. Jun 26, 2025; 17(6): 104367
Published online Jun 26, 2025. doi: 10.4252/wjsc.v17.i6.104367

Reduced NRF2/Mfn2 activity promotes endoplasmic reticulum stress and senescence in adipose-derived mesenchymal stem cells in hypertrophic obese mice

Jia Fang

Jia Fang, Henan Key Laboratory of Stem Cell Clinical Application and Key Technology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450000, Henan Province, China

Author contributions: Fang J contributed to the writing - original draft, investigation, and funding acquisition of this manuscript.

Supported by the National Natural Science Foundation of China, No. 32000511; and Medical Science and Technology Joint Construction Program of Henan Province, No. LHGJ20230053.

Institutional animal care and use committee statement: The animal experiment was approved by the Life Science Ethics Committee of Zhengzhou University. The approval number is ZZUIRB 2021-58.

Conflict-of-interest statement: The author has no conflicts of interest to declare.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: No data were used for the research described in the article.

Corresponding author: Jia Fang, Henan Key Laboratory of Stem Cell Clinical Application and Key Technology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, No. 7 Weiwu Road, Zhengzhou 450000, Henan Province, China. fangjiazd@zzu.edu.cn

Received: December 19, 2024
Revised: March 21, 2025
Accepted: May 13, 2025
Published online: June 26, 2025
Processing time: 189 Days and 1 Hours

Abstract

BACKGROUND

Hypertrophy obesity is closely associated with obesity-related metabolic diseases. The senescence of adipose-derived mesenchymal stem cells (ASCs) is believed to play a significant role in the development of hypertrophy obesity.

AIM

To investigate the relationship between ASC senescence, endoplasmic reticulum (ER) stress, and nuclear factor erythroid-derived 2 (NRF2) activity in a mouse model of hypertrophy obesity. Additionally, we explored the mechanism through which NRF2 affects ASC senescence via mitofusin-2 (MFN2).

METHODS

We observed the senescent phenotype and ER stress (ERS) in ASCs from hypertrophic obese mouse models, and determined NRF2 activity. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) was used to analyze the transcriptional activity of NRF2 on Mfn2. Additionally, co-immunoprecipitation experiments were conducted to investigate the interaction between MFN2 and binding immunoglobulin protein. The impact of NRF2 and MFN2 on the therapeutic effect of ASC transplantation against insulin resistance was explored through ASC transplantation.

RESULTS

The study found significant increases in senescence and ERS, accompanied by decreased NRF2 activity in ASCs from hypertrophic obese mouse models. Simultaneously, chromatin immunoprecipitation-qPCR analysis revealed a reduction in NRF2 transcriptional activity on Mfn2. The downregulation of NRF2 activity and Mfn2 expression promoted senescence and ERS in ASCs, subsequently impacting the anti-insulin resistance effect of ASC transplantation. Furthermore, there exists a direct or indirect binding between MFN2 and binding immunoglobulin protein.

CONCLUSION

The research outcomes suggest that NRF2 may regulate ERS and senescence in subcutaneous ASCs of hypertrophic obese mice by modulating Mfn2. These discoveries offer new insights into understanding metabolic diseases associated with hypertrophic obesity and potentially provide a foundation for intervention strategies.

Keywords: Adipose-derived mesenchymal stem cells; Senescence; Nuclear factor erythroid-derived 2; Endoplasmic reticulum stress; Mitofusin-2

Core Tip: We observed increased adipose-derived mesenchymal stem cell (ASC) senescence and endoplasmic reticulum (ER) stress, along with decreased nuclear factor erythroid-derived 2 (NRF2) activity, in a hypertrophic obese mouse model. Chromatin immunoprecipitation-quantitative polymerase chain reaction analysis revealed reduced NRF2 transcriptional activity against mitofusin-2 (Mfn2). The downregulation of NRF2 activity and MFN2 expression promoted senescence and ER stress in ASCs. Additionally, co-immunoprecipitation showed that MFN2 interacts with binding immunoglobulin protein. These findings suggest that NRF2 may regulate ER stress and senescence via MFN2 in ASCs of hypertrophic obese mice.