EPA and DHA engage NRF2 to orchestrate a β-cell resilience circuit suppressing senescence remodeling and sustaining molecular fitness during glucolipotoxic stress.
6 affiliations
- 1The Eighth Affiliated Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, Guangdong, China.
- 2Laboratory Animal Center, Sun Yat-sen University, Guangzhou, China.
- 3GuangDong Engineering Technology Research Center of Metabolic Disorders Interdisciplinary Precision Prevention and Digital Healthcare, The Eighth Affiliated Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, Guangdong, China.
- 4Center for Reproductive Medicine, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
- 5Faculty of Health Sciences, University of Macau, Macau, China.
- 6The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.
Abstract
Introduction
Preservation of pancreatic β cells under sustained glucolipotoxicity requires more than limiting cell death, because surviving cells retain stress-associated molecular abnormalities. We tested whether EPA and DHA act through an NRF2-dependent protective program in β-cell models.Methods
MIN6 cells and primary mouse islets were exposed to palmitate plus high glucose with or without EPA, DHA, or EPA+DHA. NRF2 nuclear localization, glutathione homeostasis, oxidative DNA damage, apoptosis, senescence markers, and β-cell maturity proteins were assessed, and NRF2 knockdown was used to test NRF2 dependency. Male C57BL/6J mice with established HFD/STZ diabetes received EPA, DHA, or EPA+DHA; glycemic indices and pancreatic β-cell markers were evaluated.Results
EPA and DHA increased nuclear NRF2, restored glutathione homeostasis, and reduced oxidative DNA damage, apoptotic markers, and senescence markers in both MIN6 cells and primary islets. NRF2 knockdown partially attenuated these responses, indicating that NRF2 contributes to but is not the sole mediator of the in vitro protection. In HFD/STZ mice, EPA/DHA improved glycemic indices, reduced oxidative-stress and apoptotic markers, and preserved insulin-positive β-cell area.Discussion
These findings identify an NRF2-sensitive program through which EPA and DHA preserve antioxidant capacity, survival, and maturity features of β cells under glucolipotoxic stress. Partial attenuation by NRF2 knockdown and the systemic nature of the HFD/STZ model indicate that additional NRF2-independent mechanisms contribute, and that β-cell specific NRF2 deletion will be needed to establish β-cell autonomous causality in vivo.
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BibTeX
@article{xing2026engage,
title = {{EPA and DHA engage NRF2 to orchestrate a β-cell resilience circuit suppressing senescence remodeling and sustaining molecular fitness during glucolipotoxic stress.}},
author = {Chaofeng Xing and Fanghong Li and Yan Zou and Cheng Song and Dan Luo and Jian Ruan and Minyi Tang and Qihua Xu and Yunping Mu and Jie Shen and Allan Zijian Zhao},
journal = {Frontiers in physiology},
year = {2026},
month = oct,
doi = {10.3389/fphys.2026.1948763},
url = {https://europepmc.org/article/MED/42908596},
note = {CC BY},
}
RIS
TY - JOUR
TI - EPA and DHA engage NRF2 to orchestrate a β-cell resilience circuit suppressing senescence remodeling and sustaining molecular fitness during glucolipotoxic stress.
AU - Chaofeng Xing
AU - Fanghong Li
AU - Yan Zou
AU - Cheng Song
AU - Dan Luo
AU - Jian Ruan
AU - Minyi Tang
AU - Qihua Xu
AU - Yunping Mu
AU - Jie Shen
AU - Allan Zijian Zhao
PY - 2026
DA - 2026/10/07
JO - Frontiers in physiology
DO - 10.3389/fphys.2026.1948763
UR - https://europepmc.org/article/MED/42908596
AB - Introduction Preservation of pancreatic β cells under sustained glucolipotoxicity requires more than limiting cell death, because surviving cells retain stress-associated molecular abnormalities. We tested whether EPA and DHA act through an NRF2-dependent protective program in β-cell models.Methods MIN6 cells and primary mouse islets were exposed to palmitate plus high glucose with or without EPA, DHA, or EPA+DHA. NRF2 nuclear localization, glutathione homeostasis, oxidative DNA damage, apoptosis, senescence markers, and β-cell maturity proteins were assessed, and NRF2 knockdown was used to test NRF2 dependency. Male C57BL/6J mice with established HFD/STZ diabetes received EPA, DHA, or EPA+DHA; glycemic indices and pancreatic β-cell markers were evaluated.Results EPA and DHA increased nuclear NRF2, restored glutathione homeostasis, and reduced oxidative DNA damage, apoptotic markers, and senescence markers in both MIN6 cells and primary islets. NRF2 knockdown partially attenuated these responses, indicating that NRF2 contributes to but is not the sole mediator of the in vitro protection. In HFD/STZ mice, EPA/DHA improved glycemic indices, reduced oxidative-stress and apoptotic markers, and preserved insulin-positive β-cell area.Discussion These findings identify an NRF2-sensitive program through which EPA and DHA preserve antioxidant capacity, survival, and maturity features of β cells under glucolipotoxic stress. Partial attenuation by NRF2 knockdown and the systemic nature of the HFD/STZ model indicate that additional NRF2-independent mechanisms contribute, and that β-cell specific NRF2 deletion will be needed to establish β-cell autonomous causality in vivo.
SN - 1664-042X
ER -