Exploring the roles of orphan nuclear receptors in MASLD pathogenesis

Metabolic dysfunction-associated steatotic liver disease (MASLD), affecting approximately 30% of the global population, represents a spectrum of liver disorders ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. Its pathogenesis involves complex interactions between genetic predisposition, metabolic dysregulation, inflammation, and cellular stress responses. Orphan nuclear receptors (ONRs), a subfamily of nuclear receptors lacking identified endogenous ligands, have emerged as pivotal regulators of these processes. This review explores the roles of ONRs in MASLD pathogenesis, focusing on their influence on lipid metabolism, inflammation, and autophagy, and highlights their potential as therapeutic targets.

ONR families and their roles in MASLD

1. NR0 Family (SHP and DAX-1)

   • SHP (NR0B2): Inhibits lipogenesis by suppressing SREBP-1c and Fasn expression via DNA methylation (Kim et al., 2020). It also mitigates inflammation and fibrosis by modulating chemokine CCL2 and gut microbiota (Zhou et al., 2023).

   • DAX-1 (NR0B1): Limited expression in MASLD, with unclear functional significance.

2. NR1 Family (REV-ERBs and RORs)

   • REV-ERBα (NR1D1): Attenuates steatosis by downregulating fatty acid synthesis genes (e.g., Fasn) and improving mitochondrial function (Zhong et al., 2023).

   • RORα (NR1F1): Promotes lipophagy and mitochondrial quality control, while its agonist maresin 1 reduces inflammation (Han et al., 2019).

   • RORγ (NR1F3): Contributes to lipid accumulation; inhibition by perilaldehyde alleviates steatosis (Kao et al., 2023).

3. NR2 Family (HNF4α and COUP-TFII)

   • HNF4α (NR2A1): Enhances fatty acid oxidation and autophagy (e.g., via ULK1 upregulation) but exhibits dual roles in bile acid metabolism (Roh et al., 2022). Loss exacerbates steatosis by disrupting lipid transport (Thymiakou et al., 2020).

   • COUP-TFII (NR2F2): Promotes hepatic stellate cell activation and fibrosis (Mao et al., 2024).

4. NR3 Family (ERRs)

   • ERRα (NR3B1): Drives lipogenesis and insulin resistance; its inhibition reduces steatosis (Chen et al., 2021). Paradoxically, ERRα also supports autophagy during fasting (Tripathi et al., 2024).

5. NR4 Family (Nur77 and Nurr1)

   • Nur77 (NR4A1): Reduces inflammation by polarizing macrophages to the anti-inflammatory M2 phenotype (Sun et al., 2021).

   • Nurr1 (NR4A2): Promotes fibrosis via MAPK pathway activation in hepatic stellate cells (Chen et al., 2015).

6. NR5 Family (LRH-1)

   • LRH-1 (NR5A2): Regulates phospholipid composition and bile acid metabolism. Agonists like DLPC improve steatosis and glucose homeostasis (Lee et al., 2011).

Mechanistic insights

• Lipid metabolism: ONRs modulate key pathways:

  • SHP and REV-ERBα inhibit lipogenesis (Fasn, SREBP-1c).

  • HNF4α and RORα enhance fatty acid oxidation and lipophagy.

• Inflammation: SHP and Nur77 suppress pro-inflammatory cytokines (e.g., CCL2) and promote M2 macrophage polarization.

• Fibrosis: COUP-TFII and Nurr1 activate hepatic stellate cells via MAPK signaling.

Therapeutic potential

• Natural compounds: Hyperoside (SHP activator), 6-gingerol (HNF4α agonist), and perilaldehyde (RORγ inhibitor) show efficacy in preclinical models.

• Synthetic agonists/antagonists: JND003 (ERRα agonist) and DLPC (LRH-1 agonist) improve metabolic parameters in MASLD.

• Combination strategies: Targeting multiple ONRs (e.g., FXR/SHP/SREBP-1c axis) may synergize to reduce steatosis and fibrosis.

Challenges and future directions

• Opposing roles: Some ONRs (e.g., ERRα) exhibit context-dependent effects, complicating therapeutic targeting.

• Biomarkers: Limited tools for patient stratification based on ONR activity.

• Clinical translation: No ONR-targeting drugs are yet approved for MASLD, underscoring the need for rigorous trials.

Conclusion

ONRs are central to MASLD pathogenesis, regulating lipid homeostasis, inflammation, and fibrosis through interconnected pathways. While SHP and HNF4α are well-studied, emerging targets like RORγ and LRH-1 offer novel therapeutic avenues. Future research should prioritize elucidating ONR crosstalk, developing selective modulators, and validating their efficacy in clinical settings. Harnessing ONRs may pave the way for precision medicine in MASLD, addressing its multifaceted nature.