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

Alcohol-associated liver disease (ALD) is a major global health concern, contributing to liver injury, morbidity, and mortality. Elafibranor (EFN), a dual peroxisome proliferator-activated receptor α/δ agonist, has shown promise as a therapeutic candidate in preclinical studies. EFN reduces liver fibrosis by inhibiting lipid accumulation, apoptosis, and inflammatory pathways (LPS/TLR4/NF-κB), while enhancing autophagy and antioxidant responses. It also improves intestinal barrier function and modulates gut microbiota, reducing endotoxin-producing bacteria and increasing beneficial species. By strengthening the intestinal barrier and suppressing pro-inflammatory mediators like tumor necrosis factor-alpha and interleukin-6, EFN mitigates hepatic stellate cell activation and fibrogenic signaling. Macrophages play a central role in ALD progression, and EFN's ability to modulate macrophage activity further highlights its anti-inflammatory properties. This review emphasizes EFN's dual-targeted approach, addressing both hepatic and intestinal dysfunctions, distinguishing it from conventional ALD treatments. While preclinical results are promising, EFN remains under clinical investigation, with ongoing trials evaluating its safety and efficacy. Future research should focus on elucidating EFN's molecular mechanisms and advancing its clinical application to establish its therapeutic potential in human populations. EFN represents a novel, comprehensive strategy for ALD management, targeting both liver and gut pathologies.