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Introduction: Moderate exercise induces beneficial adaptive responses in the body, whereas sustained high-intensity exercise without adequate recovery leads to overtraining syndrome (OTS), a pathological condition associated with multiple organ damage, especially liver injury. Currently, safe and effective nutritional interventions for OTS-induced liver injury remain limited. This study aimed to investigate the protective effect of ginsenoside Rb1 (Gs-Rb1), the primary bioactive component of ginseng, against OTS-induced liver injury and to elucidate its underlying molecular mechanism. Methods: We established an overtraining (OT) mouse model using ICR mice, and evaluated the hepatoprotective effect of Gs-Rb1 using histopathological observation, biochemical analysis, immunofluorescence staining, Western blot, and other related techniques. The core regulatory mechanism was verified using chloroquine (CQ, an autophagy inhibitor) and ML385 (a specific Nrf2 inhibitor). Results: OT intervention induced significant oxidative stress and liver injury in mouse liver, whereas Gs-Rb1 administration effectively alleviated liver damage, improved exercise performance, and mitigated OT-induced oxidative stress and mitochondrial impairment in the liver by activating mitophagy. Mechanistically, Gs-Rb1 promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), and further activated the downstream PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin) pathway to drive mitophagy. Inhibitor validation experiments further confirmed that the hepatoprotective effect of Gs-Rb1 was autophagy-dependent, and Nrf2 was a key regulator of Gs-Rb1-mediated mitophagy. Discussion: This study demonstrates that Gs-Rb1 ameliorates OT-induced oxidative stress in mouse liver via Nrf2-dependent mitophagy. Our findings indicate that targeting mitophagy via the Nrf2 pathway represents a promising nutritional strategy to alleviate overtraining-related liver injury, providing a theoretical basis for the application of natural bioactive compounds such as Gs-Rb1 in the field of sports nutrition and health promotion.
Lu et al. (Wed,) studied this question.