Therapeutic Targeting of AREL1 in Hepatic Stellate Cells Attenuates MASH-related Liver Fibrosis [scRNA-seq]

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 sc/snRNA sequencing data from human healthy and fibrosis samples revealed 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 attenuated 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 ameliorated MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and presents the targeted knockdown of AREL1 in HSCs represents a novel therapeutic avenue.