Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis

Fibrosis resulting from metabolic-associated steatohepatitis (MASH) is increasingly recognized as the predominant form of liver fibrosis. Although the activation of hepatic stellate cells (HSCs) is essential for liver fibrosis, the mechanisms underlying HSC activation in MASH remain inadequately understood. Integrated analysis of large-scale single-cell and single-nucleus RNA sequencing data from human healthy and fibrosis samples reveals a distinct subpopulation of HSCs in MASH. AREL1 is a characteristic gene of this subpopulation and is uniquely upregulated in MASH-related fibrosis. HSC-specific knockout of Arel1 markedly attenuates liver fibrosis in MASH model male mice. Mechanistically, AREL1 is regulated by cholesterol and facilitates HSC activation through the AREL1-ILK axis, subsequently activating the PI3K-AKT signaling pathway. Moreover, therapeutic knockdown of Arel1 using vitamin A-modified lipid nanoparticles markedly ameliorates MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and present the targeted knockdown of AREL1 in HSCs as a therapeutic avenue. Hepatic stellate cell (HSC) activation drives liver fibrosis. Here, the authors show that apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1) is upregulated in HSCs of patients with metabolic-associated steatohepatitis (MASH) and promotes fibrosis via the ILK–PI3K–AKT pathway. Targeting AREL1 with vitamin A-modified lipid nanoparticles (LNPs) reduces MASH-associated fibrosis in male mice.