Unlocking therapeutic potential: exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease.

Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other's signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field-estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)-and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.