Resmetirom, a liver-directed, orally active agonist of THR-β, could play a favorable role in treating NASH, but little is known about the underlying mechanism. A NASH cell model was established to test the preventive effect of
resmetirom on this disease in vitro.
RNA-seq was used for screening, and rescue experiments were performed to validate the target gene of the
drug. A NASH mouse model was used to further elucidate the role and the underlying mechanism of
resmetirom.
Resmetirom effectively eliminated
lipid accumulation and decreased
triglyceride (TG) levels. In addition, repressed RGS5 in the NASH model could be recovered by
resmetirom treatment. The silencing of RGS5 effectively impaired the role of
resmetirom. In the NASH mouse model, obvious gray hepatization,
liver fibrosis and
inflammation, and increased macrophage infiltration were observed in liver tissues, while
resmetirom almost returned them to normal conditions as observed in the control group. Pathological experimental data also confirmed that
resmetirom has great potential in NASH treatment. Finally, RGS5 expression was suppressed in the NASH mouse model, but it was upregulated by
resmetirom treatment, while the STAT3 and NF-κB signaling pathways were activated in NASH but inhibited by the agent.
Resmetirom could improve NASH by recovering RGS5 expression and subsequently inactivating the STAT3 and NF-κB signaling pathways.