# Nuclear Receptor-Targeted Therapies: Reprogramming Metabolism with TRβ, ERRα, and LXR Modulators

## TL;DR

This paper reviews new therapies targeting nuclear receptors TRβ, ERRα, and LXR to treat metabolic disorders like fatty liver disease and obesity.

## Contribution

The paper highlights novel small-molecule modulators for underexplored nuclear receptors with translational potential in metabolic diseases.

## Key findings

- TRβ agonists like resmetirom and TG68 show clinical efficacy in reducing liver steatosis and fibrosis.
- ERRα modulators improve insulin resistance and lipid oxidation in obesity models.
- LXRβ-selective agonists offer atheroprotective benefits without increasing triglyceride synthesis.

## Abstract

Metabolic disorders, including metabolic dysfunction-associated fatty liver disease (MAFLD), obesity, and dyslipidemia, impose a substantial and escalating global health burden, highlighting an urgent need for effective pharmacotherapies. Selective modulation of nuclear receptors (NRs) has emerged as a promising strategy to restore metabolic homeostasis. This review focuses on three therapeutically pivotal yet under-explored NRs: thyroid hormone receptor β (TRβ), estrogen-related receptor α (ERRα), and liver X receptor (LXRα/β). We critically examine recent advances in the development of small-molecule modulators for these targets and discuss their translational potential. TRβ agonists, including resmetirom (MGL-3196) and VK2809, have demonstrated compelling efficacy in clinical trials for metabolic dysfunction-associated steatohepatitis (MASH), significantly reducing hepatic steatosis and fibrosis. Next-generation hepatoselective modulators such as TG68 enhance tissue specificity and potency. ERRα, a master regulator of mitochondrial biogenesis and energy metabolism, is targeted by inverse agonists (compound 29, GSK5182) and agonists (JND003, SLU-PP-915), which show promise in ameliorating insulin resistance and promoting lipid oxidation in preclinical obesity models. LXRs, central players in cholesterol homeostasis, are the focus of innovative drug design aimed at harnessing atheroprotective benefits via LXRβ-selective or partial agonists, thereby circumventing adverse effects on triglyceride synthesis. Collectively, the ongoing development of TRβ, ERRα, and LXR modulators exemplifies a new frontier in precision medicine, offering powerful approaches to reprogram dysregulated metabolic pathways with substantial promise for treating metabolic diseases.