Nrf2 in obesity: Mechanisms, models, and bioactive modulators

Obesity is a chronic disease characterized by persistent low-grade inflammation, oxidative stress, and profound metabolic dysregulation, representing a major global health challenge. Among the key molecular players implicated in these processes is nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular redox homeostasis and cytoprotective responses. In recent years, growing evidence has identified Nrf2 as a central node linking inflammation, oxidative stress, adipogenesis, and lipid metabolism in the development and progression of obesity. This review provides an integrated overview of current insights into the mechanistic roles of Nrf2 in these processes, incorporating findings from genetic and pharmacological models and discussing its dual, context-dependent effects on obesity-related pathways. Special emphasis is placed on highlighting both protective and adverse outcomes of Nrf2 modulation. Furthermore, the review presents a comprehensive summary of bioactive compounds, both synthetic and natural, that may activate Nrf2 and exert anti-obesity effects. Some of these compounds have undergone clinical trials and represent promising leads for the development of Nrf2-targeted interventions in obesity. However, current clinical evidence remains limited and is derived mainly from studies on metabolic syndrome, type 2 diabetes, and fatty liver disease rather than obesity-focused trials. The review also identifies limitations and gaps that must be addressed before preclinical findings can be effectively translated into clinical applications. Collectively, the review underscores both the therapeutic potential and the complexity of Nrf2 signaling modulation in obesity, while emphasizing the need for further mechanistic and clinical studies to better define safe and effective Nrf2-targeted strategies.