Dihydromyricetin attenuates cholestatic liver injury by suppressing JAK2/STAT3-associated NF-κB inflammatory and apoptotic signaling.
TL;DR
Dihydromyricetin alleviates CLI by suppressing inflammation, oxidative stress, and hepatocyte apoptosis, at least partly through inhibition of the JAK2/STAT3-NF-κB signaling axis.
Abstract
Background
Cholestatic liver injury (CLI) is mainly driven by hepatic bile acid accumulation, which promotes hepatocyte injury, inflammation, oxidative stress, and apoptosis. Dihydromyricetin (DHM), a bioactive flavonoid from Ampelopsis grossedentata, has shown hepatoprotective potential, but its role and mechanism in CLI remain unclear.
Methods
Network pharmacology, public transcriptomic analysis, and molecular docking were used to predict candidate targets of DHM in CLI. Taurocholic acid (TCA) treated HepaRG cells and α-naphthylisothiocyanate (ANIT)-treated mice were used as in vitro and in vivo models, respectively, with ursodeoxycholic acid (UDCA) included as a positive control. Hepatic injury, inflammation, oxidative stress, apoptosis, JAK2/STAT3-associated NF-κB signaling, bile acid-related molecules, and ductular reaction markers were assessed. AG490-mediated pathway inhibition and IL-6-mediated STAT3 reactivation were performed to assess the functional involvement of STAT3 signaling.
Results
DHM improved cell viability and reduced TCA-induced ALT, AST, LDH, ALP, and inflammatory cytokine levels. Network pharmacology identified STAT3, AKT1, SRC, ESR1, and MMP9 as hub targets, while public transcriptomic and enrichment analyses highlighted inflammation-, apoptosis-, NF-κB-, and JAK/STAT-related pathways. DHM attenuated TCA-induced apoptosis and suppressed JAK2/STAT3-associated NF-κB activation, including reduced p65 nuclear translocation. DHM also regulated bile acid homeostasis-related molecules in vitro. In ANIT-treated mice, DHM improved liver histology, decreased ALT, AST, ALP, TBA, inflammatory cytokines, and oxidative stress, and suppressed hepatic apoptosis and JAK2/STAT3-NF-κB signaling. AG490 phenocopied the protective effects of DHM, whereas IL-6-mediated STAT3 reactivation partially weakened DHM-mediated protection.
Conclusion
DHM alleviates CLI by suppressing inflammation, oxidative stress, and hepatocyte apoptosis, at least partly through inhibition of the JAK2/STAT3-NF-κB signaling axis.