Tectorigenin Mediates miR-338-3p/AATK Axis to Prevent Fulminant Hepatic Failure

Abstract

Background: Tectorigenin can impede inflammation, cell apoptosis, and has hepatoprotective effects. This study was designed to elucidate how Tectorigenin impacts fulminant hepatic failure (FHF). Methods: Intraperitoneal injections of lipopolysaccharide (LPS; 50 μg/kg) and d-galactosamine (d-GalN; 300 mg/kg) were applied to establish an FHF rat model. FHF rats were given different concentrations of Tectorigenin (12.5, 25 and 50 mg/kg) before LPS/d-GalN treatment. Histological analysis was achieved through Hematoxylin-eosin (H&E) and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, followed by detection of serum factor levels by using Enzyme-linked immunosorbent assay (ELISA). BRL cells were treated with 200 μM H₂O₂ (48 h) to induce the FHF model in vitro. After BRL cells were treated with H₂O₂, Tectorigenin (200 μM) and transfected with miR-338-3p inhibitor or small interfering (si)-apoptosis-associated tyrosine kinase (AATK), the apoptotic factors, inflammatory factors, miR-338-3p and AATK expression levels, and biological function were evaluated by real-time quantitative PCR (RT-qPCR), western blot, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry. TargetScan v7.2 prediction and dual luciferase assay were performed for target relationship verification. Results: Tectorigenin reduced histopathological damage, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory factors, apoptosis, mortality, and AATK protein expression, while increasing miR-338-3p mRNA levels in vivo (p < 0.001). Tectorigenin exerted the opposite effects of H₂O₂ on cell viability, cell cycle, cell apoptosis and inflammatory factors. The effect of Tectorigenin was reversed by miR-338-3p inhibitor. Furthermore, there was a targeting relationship between miR-338-3p and AATK and a negative interplay between miR-338-3p inhibitor and siAATK on the above-mentioned biological behaviors. Conclusions: Tectorigenin may protect against FHF through the miR-338-3p/AATK cascade.