Vesnu Publications (Farzanegan Radandish) Journal of Exercise & Organ Cross Talk 2783-2074 Articles in Press 2026 09 01 High-Intensity Interval Training and Ketone Ester Supplementation Attenuate Hepatic Oxidative Stress and Inflammation Through Modulation of the Keap1/Nrf2/NF-κB Axis in Western Diet-Fed Mice 245762 10.22122/jeoct.2026.584193.1207 EN Maryam Sarsangi Aliabad Department of Sport Sciences, Faculty of Humanities, University of Kashan, Kashan, Iran 0009-0004-5263-0941 Mousa Khalafi Department of Sport Sciences, Faculty of Humanities, University of Kashan, Kashan, Iran 0000-0001-6465-1281 Aref Habibi Maleki Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran 0000-0001-7715-0734 Journal Article 2026 05 01 Western diet (WD) consumption promotes oxidative stress and inflammation and plays a central role in the development of fatty liver disease. This study investigated the effects of high-intensity interval training (HIIT), ketone ester supplementation, and their combination on hepatic Keap1, Nrf2, and NF-κB protein levels in WD-fed mice. Thirty male C57BL/6J mice were randomly assigned to five groups (n=6): normal diet (ND), WD, WD plus ketone ester (WD+KE), WD plus HIIT (WD+HIIT), and WD plus HIIT combined with ketone ester supplementation (WD+HIIT+KE). Except for the ND group, all animals consumed a WD for eight weeks. HIIT was performed for four weeks (three sessions/week), and ketone ester was administered daily by oral gavage. Hepatic protein levels of Keap1, Nrf2, and NF-κB were determined using Western blotting. WD feeding significantly increased hepatic Keap1 and NF-κB protein levels and reduced Nrf2 levels compared with the ND group. HIIT and ketone ester, both independently and in combination, significantly decreased NF-κB and increased Nrf2 protein levels compared with the WD group. In addition, HIIT alone and in combination with ketone ester supplementation significantly reduced hepatic Keap1 levels (p<0.05). Overall, both interventions alleviated WD-induced alterations in hepatic oxidative stress and inflammatory signaling. The combined intervention elicited the most pronounced molecular responses, suggesting potential synergistic effects of HIIT and ketone ester supplementation in attenuating Western diet-induced oxidative stress and inflammation.