IGF2BP3 regulates macrophage-induced inflammation and liver damage in acute-on-chronic liver failure via the RORα-NF-κB signaling axis

Acute-on-chronic liver failure (ACLF) is a severe condition characterized by high mortality rates, and macrophage-mediated inflammation plays a critical role in its progression. Our previous research has indicated the involvement of the RNA-binding protein IGF2BP3 in the pathogenesis of ACLF. However, the underlying molecular mechanisms contributing to this damage require further elucidation. Initially, we observed heightened expression of pro-inflammatory cytokines and macrophage activation in both ACLF patients and a mouse model induced by D-GalN/LPS. Subsequent loss-of-function experiments targeting IGF2BP3 revealed that the knockdown of IGF2BP3 potentially confers hepatoprotection by mitigating macrophage-induced inflammation. Further investigation using RNA Immunoprecipitation (RIP) assays and dual luciferase reporter assays confirmed that ROR alpha is a target protein of the RNA-binding protein IGF2BP3. Importantly, depletion of ROR alpha was found to significantly increase liver damage and inflammation by modulating the NF-kappa B kappa B signaling pathway. In conclusion, our findings underscore the crucial role of IGF2BP3 in mediating liver damage induced by activated macrophages in ACLF, which is regulated by the ROR alpha-NF-kappa B kappa B signaling pathway. These discoveries offer novel insights into the pathogenesis and potential therapeutic targets for ACLF.