Morroniside Ameliorates High-Fat and High-Fructose-Driven Chronic Kidney Disease by Motivating AMPK–TFEB Signal Activation to Accelerate Lipophagy and Inhibiting Inflammatory Response

Studies have substantiated that dietary-fat- and fructose-overconsumption-caused lipid metabolism disorders can trigger renal lipotoxicity to drive the progression of chronic kidney disease (CKD). This study was conducted to evaluate the efficacy of morroniside, a natural active substance extracted from the fruit of <i>Cornus officinalis</i>, in inhibiting the progression of CKD in high-fat and high-fructose-fed mice. Our results showed histological changes such as fatty degeneration of renal tubular cells, tubular dilatation, glomerular fibrosis, and abnormal renal function in the kidneys of high-fat- and high-fructose-fed mice, which was significantly improved after morroniside treatment. Mechanistically, morroniside maintained renal lipid metabolism homeostasis and inhibited NLRP3 inflammatory vesicle activation by activating AMPKα to promote TFEB nuclear translocation-mediated lipophagy. Consistent results were observed in palmitic acid-induced HK-2 cells. Notably, silencing AMPKα or TFEB both reversed the effects of morroniside in promoting lipophagy and inhibiting the activation of inflammatory responses in vivo and in vitro. Therefore, our study provides compelling evidence that morroniside delays CKD progression by promoting AMPK/TFEB-mediated lipophagy and inhibiting NLRP3 inflammasome activation, suggesting that dietary supplementation with morroniside and morroniside-rich foods (such as <i>Cornus officinalis</i>) might be an effective strategy for the prevention of CKD.