2. Academic Validation
  3. Acute exercise activates hepatic Nrf2 signaling by ROS, AMPK and epinephrine to protect against acute liver injuries

Acute exercise activates hepatic Nrf2 signaling by ROS, AMPK and epinephrine to protect against acute liver injuries

  • Toxicol Appl Pharmacol. 2026 Jun:511:117799. doi: 10.1016/j.taap.2026.117799.
Simin Yang 1,  Ranting Zhao 2,  Li Lei 3,  Xiangbo An 4,  Jiangli Xu 3,  Han Xu 3,  Jiahui Wang 3,  Han Xiao 4,  Youyi Zhang 4,  Xiaoda Yang 3,  Siwang Yu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China,; Beijing Key Laboratory of Enze Biomass Fine Chemicals, Beijing Institute of Petrochemical Technology, Beijing, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China,; Key Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, Peking University Health Science Center, Beijing 100191, PR China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China.
  • 4 Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China,; Key Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: [email protected].
PMID: 41861854 DOI: 10.1016/j.taap.2026.117799
Abstract

While exercise is well-established as a protective strategy against non-alcoholic fatty liver disease, its role in acute liver injury (ALI) remains poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant response element (ARE)-dependent gene expression, plays an important role in the pathogenesis of liver diseases, where oxidative stress contributes significantly to both chronic progression and acute injury. This study investigated whether exercise confers protection against ALI via the Nrf2 signaling pathway and elucidated the underlying molecular mechanisms. We found that acute treadmill exercise time- and intensity-dependently activated hepatic Nrf2 signaling in mouse, conferring significant protection against ALI induced by alcohol, acetaminophen, or carbon tetrachloride. Conversely, exercise failed to protect against and even exacerbated ALI in Nrf2-deficient mice. Furthermore, using antioxidant Trolox and AMPKα2-knockout mice, we demonstrated that exercise activated hepatic Nrf2 primarily via ROS and AMPK signaling. Additionally, we identified exercise-induced elevation of epinephrine as a novel mechanism for activating hepatic Nrf2. In conclusion, our study demonstrates that exercise protects against ALI by activating the hepatic Nrf2/ARE signaling axis and delineates the associated molecular mechanisms, providing a scientific rationale for exercise-based therapeutic interventions.

Keywords

Acetaminophen; Alcohol; Carbon tetrachloride; Exercise; Hepatotoxicity; Nrf2.

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