ChREBP-?/TXNIP aggravates frucose-induced renal injury through triggering ferroptosis of renal tubular epithelial cells

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-beta 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-beta in the renal tubule was established by using the Cre/LoxP method. Quantitative proteomic analysis and experimental verification results suggest that ChREP-beta overexpression leads to ferroptosis of renal tubular epithelial cells and kidney injury. ChREPB-beta 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-beta, metformin can inhibit gene transcription of TXNIP, attenuate high fructose-induced ferroptosis in renal tubular epithelial cells, and alleviate kidney injury. In conclusion, ChREBP-beta mediates fructose-induced ferroptosis of renal tubular epithelial cells, and metformin with a ChREBP-beta inhibitory effect may be a potential treatment for ferroptosis of renal tubular epithelial cells.

Automated summary

High fructose intake is a risk factor for kidney injury, and the specific mechanism is still unclear. ChREBP-beta, an active form of ChREBP, is involved in the regulation of fructose metabolism. Overexpression of ChREP-beta leads to ferroptosis and kidney injury in renal tubular epithelial cells. TXNIP, which is upregulated by ChREP-beta, is associated with ferroptosis. Metformin can inhibit the transcription of TXNIP by down-regulating ChREP-beta, thus alleviating high fructose-induced ferroptosis and kidney injury.