Depletion of Igfbp7 alleviates zebrafish NAFLD progression through inhibiting hepatic ferroptosis

The global increased expression of Insulin-like growth factor binding protein 7 (IGFBP7) has been detected in non-alcoholic fatty liver disease (NAFLD) patients, however, its roles in NAFLD and the mechanism remain largely unclear. The goal of this study is to investigate the effect and mechanism of Igfbp7 using a zebrafish NAFLD model.The igfbp7-/- null zebrafish mutant and the Igfbp7 liver overexpressed (LOE) transgenic zebrafish based on Gal4/UAS system were generated by CRISPR/Cas9 and Tol2 transgenic technique, respectively. The zebrafish NAFLD models in wildtypes, igfbp7-/- mutants and Igfbp7 LOE fishes have been established by high-fat diet feeding. The Igfbp7 dynamic expression and its effects on NAFLD progression have been detected and analyzed in both human NAFLD patients and zebrafish models. And the potential mechanism has been investigated through transcriptome analysis and subsequent detection and verification.High Igfbp7 levels in NASH and fibrosis stages have been detected in liver tissues of both human NAFLD patients and zebrafish models. Depletion of Igfbp7 significantly alleviated liver steatosis, inflammation, and fibrosis, whereas liver specific Igfbp7 overexpression dramatically exacerbated liver fibrosis in zebrafish NAFLD model. The hepatic iron deposition, lipid peroxidation products, and ferroptosis-related index were also significantly reduced at the NASH stage in the absence of Igfbp7. Igfbp7 promotes NAFLD progression through regulating ferroptosis, and Ncoa4-mediated ferritinophagy may be the pathway of Igfbp7-regulated ferroptosis.Igfbp7 is confirmed as an important regulator in NAFLD progression. Depleting Igfbp7 effectively alleviates zebrafish NAFLD progression by inhibiting hepatic ferroptosis, suggesting a novel potential target for NAFLD treatment.