Fang J. Reduced NRF2/Mfn2 activity promotes endoplasmic reticulum stress and senescence in adipose-derived mesenchymal stem cells in hypertrophic obese mice. World J Stem Cells 2025; 17(6): 104367 [PMID: 40585950 DOI: 10.4252/wjsc.v17.i6.104367]
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05292747
Submitted on:
July 04, 2025, 02:30
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Reader Comments:
This study demonstrates that reduced NRF2 activity contributes to ER stress and senescence in adipose-derived mesenchymal stem cells (ASCs) from hypertrophic obese mice, primarily through downregulation of MFN2.
The use of multiple approaches, including NRF2/MFN2 knockdown and rescue, ChIP-qPCR, Co-IP, immunofluorescence, and IP-MS, adds robustness to the findings. Importantly, the functional relevance is strengthened by transplantation experiments, showing that disruption of NRF2 or MFN2 impairs the therapeutic potential of ASCs in insulin resistance, highlighting translational significance.
However, while the authors suggest an interaction between MFN2 and BIP, the evidence remains indirect. Biochemical confirmation such as GST pull-down or FRET would be needed to verify a direct interaction. Additionally, NRF2 may affect ER stress and senescence through other targets beyond MFN2, which were not explored in this study.
Future work should aim to clarify the structural basis of MFN2–BIP interaction and its functional consequences. Given the known role of MFN2 in mitochondrial dynamics and ER-mitochondrial tethering, investigating how this axis influences mitochondrial morphology, mitochondria-associated membranes integrity, and calcium signaling could provide further mechanistic insights.
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