EPA and DHA engage NRF2 to orchestrate a β-cell resilience circuit suppressing senescence remodeling and sustaining molecular fitness during glucolipotoxic stress.

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 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