Therapeutic potential of elafibranor in alcohol-associated liver disease: Insights into macrophage modulation and fibrosis reduction

Table 1 Mechanisms of elafibranor in alcohol-associated liver disease

Mechanism	Target/effect	Benefit in ALD	Translational implications
PPARα activation	Stimulates fatty acid breakdown (lipolysis) and β-oxidation	Reduces hepatic steatosis	Potential target for reducing liver fat accumulation in ALD patients
	Promotes autophagy	Mitigates oxidative stress	Enhances cellular repair mechanisms in ALD-related damage
	Upregulates antioxidant genes	Maintains cellular homeostasis	May prevent disease progression and hepatocyte injury
		Reduces hepatic injury and inflammation	Could serve as a therapeutic strategy to limit liver damage
PPARδ activation	Enhances tight junction protein expression (intestinal barrier integrity)	Reduces intestinal permeability	Prevents endotoxin leakage, reducing inflammation in ALD
	Promotes intestinal epithelial cell autophagy	Prevents endotoxin translocation	Protects gut-liver axis and limits systemic inflammation
	Reduces intestinal apoptosis	Maintains intestinal barrier function	Prevents gut-derived inflammation in ALD pathogenesis
		Reduces inflammation and systemic effects	Could lower systemic complications associated with ALD
Macrophage activity	Reduces M1 macrophage markers (pro-inflammatory)	Suppresses TLR4/NF-κB signaling	Decreases inflammation-driven liver damage
	Promotes M2 macrophage marker (anti-inflammatory)	Shifts macrophage phenotype to anti-inflammatory state	Could be harnessed for immunomodulation in ALD therapy
	Reduces hepatic pro-inflammatory cytokine expression	Attenuates liver fibrosis	Potential strategy to prevent fibrosis progression
Other mechanisms	Decreases LPS binding protein and CD14 expression (reduces LPS signaling)	Reduces inflammation	Targets gut-derived inflammation, a key factor in ALD
	Influences bile acid metabolism	Potentially reduces hepatic lipid accumulation	May improve metabolic balance in ALD patients
	Regulates Kupffer cell activity	Mitigates liver damage and fibrosis	Modulating Kupffer cells could be a therapeutic approach for ALD
	Induces fibroblast growth factor 21 expression (anti-inflammatory and metabolic regulation)	Further modulates inflammatory responses and metabolic processes	Could be explored for systemic metabolic benefits in ALD

ALD: Alcohol-associated liver disease; LPS: Lipopolysaccharides; PPAR: Peroxisome proliferator-activated receptor.