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Unlocking therapeutic potential: exploring cross-talk among emerging nuclear receptors to combat metabolic

Milton Boaheng Antwi1,2,3,4, Ariann Jennings5, Sander Lefere2,3

  • 1Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium.

Npj Metabolic Health and Disease
|July 2, 2025
PubMed

Insights

Nuclear receptors (NRs) are key targets for metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Understanding NR crosstalk offers new therapeutic strategies for these liver conditions.

Area of Science:

  • Hepatology and Endocrinology
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear receptors (NRs) are crucial regulators of cellular processes and emerging therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH).
  • The complex interplay between different NRs represents an underexplored area in MASLD and MASH pharmacotherapy.

Purpose of the Study:

  • To review emerging and established NRs involved in MASLD and MASH.
  • To elucidate the crosstalk between NRs and their collective impact on liver pathophysiology.
  • To explore the therapeutic potential of targeting NR pathways for MASLD and MASH treatment.

Main Methods:

  • Literature review of emerging NRs: estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR).
  • Analysis of interplay with established NRs: PPARs, FXR, LXR, HNF4α, and THRβ.
  • Examination of NR crosstalk mechanisms (direct and indirect) and their effects on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis.

Main Results:

  • Identified key emerging NRs (ERRα, GR, ERα, LRH-1, VDR) and their interactions with established NRs (PPARs, FXR, LXR, HNF4α, THRβ).
  • Demonstrated the collective impact of NR signaling on critical pathways in MASLD and MASH.
  • Highlighted findings on dual NR crosstalk influencing disease progression.

Conclusions:

  • Elucidating NR interactions provides novel insights into MASLD and MASH pathogenesis.
  • Targeting specific NR pathways with modulators offers promising therapeutic avenues.
  • Further research into NR crosstalk is critical for advancing hepatology and developing effective treatments for MASLD and MASH.

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