Nrf2 as a therapeutic target of ginseng: A comprehensive review from preclinical evidence to clinical applications.

Ginseng is a traditional herb that has been widely used for centuries to treat various diseases. A key mechanism of ginseng is the activation of nuclear factor erythroid 2-like 2 (Nrf2), a master regulator of antioxidant gene expressions. Activation of Nrf2 helps maintain redox homeostasis, which is crucial for chronic disease management. This review aims to summarize the pleiotropic role of Nrf2 in mediating the biological effects of bioactive compounds, extracts, and formulations of ginseng. It provides a comprehensive overview of current research on the medicinal applications of ginseng for treating various diseases and highlights the mechanisms involved in Nrf2 regulation. The literature published from 2018 to 2025 were reviewed using a PubMed search to assess recent studies on the therapeutic applications of ginseng mediated by Nrf2. Ginseng activates the Nrf2 signaling pathway and modulates its upstream signaling, including Kelch-like ECH-associated protein 1 (Keap1), p62, and glycogen synthase kinase-3β (GSK-3β). It exhibits anti-oxidative stress, anti-inflammation, anti-apoptosis, anti-ferroptosis, and anti-pyroptosis properties in both in vitro and in vivo disease models. The causal relationship between Nrf2 regulation and the protective effects of ginseng was demonstrated in Nrf2/its upstream regulators knockout and knockdown models. Clinical studies including those on Korean red ginseng (KRG) and Shenmai Injection (SMI) have validated the safety and efficacy of ginseng in improving several pathological conditions. The pleiotropic pharmacological effects of ginseng are attributed to Nrf2 activation and stabilization. These findings offer significant potential for the therapeutic applications of ginseng.