Ginsenoside F4 attenuates obesity-associated tendon pathology through AMPK/Nrf2-associated suppression of metabolic stress

Aim Obesity-associated tendinopathy is influenced by mechanical overload and metabolic stress, including oxidative imbalance and inflammation. This study investigated whether ginsenoside F4 (GF4), a bioactive metabolite of Panax ginseng , attenuates obesity-associated tendon pathology and palmitate-induced tenocyte injury, and explored the involvement of AMPK-associated signaling. Methods Collagenase-induced Achilles tendon pathology was established in high-fat diet (HFD)-fed mice, and GF4 was administered orally for 2 or 6 weeks. Tendon pathology, oxidative stress, inflammatory cytokines, and AMPK/Nrf2-related signaling were evaluated. In vitro, palmitate-treated primary human tenocytes were used to model metabolic stress. Apoptosis, oxidative stress, inflammatory responses, ECM degradation-associated changes, and migration-related cellular responses were assessed with or without GF4. AMPK involvement was evaluated using siRNA-mediated knockdown. Results GF4 attenuated collagenase-induced tendon degeneration in obese mice and decreased inflammatory-cell infiltration, MDA, H 2 O 2 , circulating TNFα, and MCP-1 levels. Long-term GF4 administration attenuated HFD-induced body weight gain. In palmitate-exposed tenocytes, GF4 increased viability, decreased caspase-3 activity and TUNEL-positive apoptosis, suppressed ROS production and lipid peroxidation, reduced NFκB p65/IκBα phosphorylation and cytokine release, improved migration-related responses, and attenuated ECM degradation-associated changes. GF4 also increased AMPK phosphorylation, Nrf2 expression, and antioxidant enzyme activity. In tenocytes, AMPK knockdown attenuated these effects, supporting the involvement of AMPK-associated signaling. Conclusion GF4 attenuated collagenase-induced tendon pathology in obese mice and reduced palmitate-associated tenocyte injury in vitro, with effects associated with increased AMPK phosphorylation, increased Nrf2 expression, reduced oxidative stress, and decreased NFκB p65/IκBα phosphorylation.