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

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.