Raspberry Ketone protects against type 2 diabetes mellitus-related lipotoxicity by suppressing ferroptosis via activation of the DJ-1/Nrf2 pathway

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease, and dietary intervention is a fundamental strategy for its prevention. Raspberry ketone (RK) is a natural aromatic compound that comes from red fruits and berries, known for its hepatoprotective and hypoglycemic effects. However, the precise mechanism and direct target of RK in T2DM intervention remain unclear. This study aimed to elucidate how RK mitigates high-glucose-high-fat (HGHF)-induced lipotoxicity and ferroptosis, and to explore its potential implications for T2DM treatment. AML12 cell lines exposed to HGHF conditions and a T2DM mouse model induced by a high-fat diet (HFD) combined with streptozotocin (STZ) were used to investigate RK’s protective effects. The results indicated that RK significantly alleviated lipotoxicity and ferroptosis in HFD/STZ-treated mice, as demonstrated by increased glutathione (GSH) and superoxide dismutase (SOD) expression, along with decreased malondialdehyde (MDA) levels. Furthermore, RK notably inhibited reactive oxygen species (ROS) production and apoptosis in AML12 cells under HGHF conditions. Mechanistically, RK activated the DJ-1/Nrf2 pathway, whereas DJ-1 knockdown using siRNA (siRNA-DJ-1) reversed these beneficial effects. Thus, DJ-1 is a crucial target of RK in AML12 cells and the T2DM mouse model. Consequently, RK represents a promising therapeutic approach for T2DM by targeting the DJ-1/Nrf2 pathway to reduce lipotoxicity and ferroptosis.