Daphnetin attenuates the early stage of adipogenesis via suppressing mitotic clonal expansion through Nrf2-mediated redox regulation.

Obesity is a major metabolic disorder closely associated with redox imbalance and excessive adipose tissue expansion, yet safe and effective natural compounds targeting early adipogenic events remain limited. Daphnetin, a naturally occurring coumarin derived from edible plants with reported antioxidant properties, has not been fully characterized in the context of adipocyte differentiation and obesity development. Here, we demonstrate that daphnetin significantly attenuates both diet-induced and genetically induced obesity in mice, as evidenced by reduced adiposity and improved glucose homeostasis, without affecting food intake or inducing detectable toxicity. Mechanistically, daphnetin suppresses adipogenesis by targeting mitotic clonal expansion (MCE), a critical early stage of adipocyte commitment. Further investigation revealed that daphnetin effectively modulates intracellular redox homeostasis by reducing reactive oxygen species (ROS) accumulation and promoting nuclear translocation of Nrf2 during adipocyte differentiation. Restoration of oxidative stress by exogenous H2O2 abolished the inhibitory effects of daphnetin on MCE and adipogenesis. Consistently, genetic knockdown or pharmacological inhibition of Nrf2 reversed daphnetin-mediated antioxidant signaling and rescued adipogenic progression. Collectively, these findings identify a previously unrecognized Nrf2-ROS-MCE regulatory axis as a key target of daphnetin in adipocyte biology. This study highlights early-stage redox modulation by natural dietary-derived compounds as a promising strategy for preventing obesity and associated metabolic disorders.