High fructose consumption can result in ferroptosis in renal tubular epithelial cells.

High fructose causes ferroptosis in renal tubular epithelial cells via ChREBP-β/TXNIP axis.

Metformin alleviates fructose-induced kidney damage by regulating the ChREBP-β/TXNIP axis.

High fructose intake is an essential risk factor for kidney injury. However, the specific mechanism underlying high fructose-induced kidney injury remains unclarified. Carbohydrate response element-binding protein (ChREBP) is a key transcriptional activator that regulates fructose metabolism. ChREBP-β exhibits sustained activity due to the lack of a low glucose inhibitory domain, and is thus described as the active form of ChREBP. In this study, a mouse model with specific overexpression of ChREBP-β in the renal tubule was established by using the Cre/LoxP method. Quantitative proteomic analysis and experimental verification results suggest that ChREP-β overexpression leads to ferroptosis of renal tubular epithelial cells and kidney injury. ChREPB-β promotes the gene transcription of thioredoxin-interacting protein (TXNIP) and thereby increases its expression level. TXNIP is associated with activation of ferroptosis. TXNIP can initiate ferroptosis and eventually contribute to high fructose-induced renal tubular epithelial cell damage. Through down-regulating ChREBP-β, metformin can inhibit gene transcription of TXNIP, attenuate high fructose-induced ferroptosis in renal tubular epithelial cells, and alleviate kidney injury. In conclusion, ChREBP-β mediates fructose-induced ferroptosis of renal tubular epithelial cells, and metformin with a ChREBP-β inhibitory effect may be a potential treatment for ferroptosis of renal tubular epithelial cells.

High fructose

Ferroptosis

Kidney injury

ChREBP-β

TXNIP

© 2023 The Authors. Published by Elsevier Inc.