Unveiling the sweet culprit: Excessive fructose intake leading to kidney injury through hypoxanthine accumulation

Fructose, a frequent-using sweeter, has been widely used in the food and beverage industry. Notably, prolonged consumption of fructose-rich diets has been recognized as a culprit causing kidney injury. However, it remains elusively obscure whether excessive fructose intake resulted in hypoxanthine (HX) accumulation and further induced kidney injury. Therefore, the present work made a pioneering endeavor to unravel the potential material basis of fructose-induced kidney injury and further probed its underlying pathogenic mechanism. Results indicated that long-term high-fructose intake contributed to HX accumulation, which subsequently triggered inflammation and oxidative damage. Moreover, further mechanistic investigations suggested that accumulated HX inhibited nuclear factor-erythroid-2-related factor 2 (Nrf2) nuclear translocation and consequently down-regulated expressions of downstream antioxidant proteins. Additionally, it effectively promoted NOD-like receptor 3 (NLRP3) inflammasome activation. Altogether, these findings suggested that excessive fructose consumption facilitated HX accumulation, which further aggravated kidney injury, at least in part, via modulating the Keap1-Nrf2/NLRP3 signaling axis.