Resmetirom Ameliorates NASH-Model Mice by Suppressing STAT3 and NF-κB Signaling Pathways in an RGS5-Dependent Manner

Abstract

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.

Synthesis and biological evaluation of the novel chrysin prodrug for non-alcoholic fatty liver disease treatment

“…Currently, there are still no approved drugs for the treatment of NAFLD. Notably, resmetirom, a thyroid hormone receptor-β agonist developed by Madrigal for the treatment of NASH with liver fibrosis, was granted breakthrough therapy designation in April 2023 by the FDA (Karim and Bansal, 2023;Wang et al, 2023). Otherwise, the current state of drug development for NAFLD remains unsatisfactory (Banini and Sanyal, 2017;Fang et al, 2022;Umemura et al, 2022).…”

Safety and efficacy of resmetirom in the treatment of patients with non-alcoholic steatohepatitis and liver fibrosis: a systematic review and meta-analysis

“…A pooled analysis of three studies reveals a noteworthy reduction in ALT and AST levels with Resmetirom treatment compared to placebo, indicating improved liver function, reduced hepatic inflammation, and overall enhanced liver health. Additionally, Resmetirom demonstrates a significant impact on NASH biomarkers, suggesting efficacy in modulating key underlying causes through the modulation of lipophagy, mitophagy, and mitogenesis within hepatocytes 25 . Navigating the diagnostic landscape of NASH proves challenging, often leading to late-stage identification utilizing invasive techniques like liver biopsy.…”

Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD

“…These clinical observations were confirmed in a mouse model of Diet-induced NASH by Kannt et al, in which resmetirom had similar effects both in liver fat content and in lipid profile [ 165 ]. Wang et al recently determined that the action of resmetirom is also mediated by the suppression of STAT3 and NFkB signalling through the activation of RGS5 in mice, suggesting a new collateral target for NASH treatment [ 166 ]. A promising phase 3 clinical trial with resmetirom is currently ongoing (MAESTRO-NASH NCT03900429), and the treatment efficacy on fibrosis will also be evaluated after 52 weeks [ 167 ].…”