Background: Metabolic dysfunction-associated steatohepatitis (MASH) is a frequent consequence of Western diet consumption and liver steatosis. IL-18 binding protein (IL-18BP) limits the action of interleukin-18 (IL-18). Our work aims to study the unknown role of IL-18BP in MASH progression.

Methods: We analyzed the liver transcriptome from MASH patients. We investigated cell-specific expressions of IL-18, IL-18BP, and IL-18 receptor in human and mouse liver. We studied the liver phenotype of Il18bp-/- mice on a high-fat/high-cholesterol (HFHC) diet. We administered an anti-IL-18 antibody in Il18bp-/- mice and in diet-induced wild-type (WT) MASH mice. We generated and studied double knock-out Il18bp-/-Ifng-/- mice.

Results: IL-18BP expression is increased in the liver of patients and mouse models with MASH and positively correlates with fibrosis stages. On the HFHC diet, Il18bp-/- mice exhibit increased hepatic damage, inflammation, and fibrosis compared with WT mice. Treatment with anti-IL-18 antibody corrects liver defects in Il18bp-/- mice and ameliorates inflammation and fibrosis in diet-induced MASH mice, suggesting a translational treatment opportunity. Genetic deficiency in IFN-γ abrogates inflammation but not fibrosis in Il18bp-/- mice.

Conclusions: IL-18BP has a role in limiting the progression of MASH, notably by reducing inflammation and fibrosis. Downstream IL-18 over-signaling, IFN-γ, mediates inflammation, but not fibrosis. Increasing IL-18BP levels represents a novel therapeutic perspective for patients affected by MASH.