Abstract The mechanisms underlying liver fibrosis are multifaceted and remain elusive with no approved antifibrotic treatments available. The adult zebrafish has been an underutilized tool to study liver fibrosis. We aimed to characterize the single‐cell transcriptome of the adult zebrafish liver to determine its utility as a model for studying liver fibrosis. We used single‐cell RNA sequencing (scRNA‐seq) of adult zebrafish liver to study the molecular and cellular dynamics at a single‐cell level. We performed a comparative analysis to scRNA‐seq of human liver with a focus on hepatic stellate cells (HSCs), the driver cells in liver fibrosis. scRNA‐seq reveals transcriptionally unique populations of hepatic cell types that comprise the zebrafish liver. Joint clustering with human liver scRNA‐seq data demonstrates high conservation of transcriptional profiles and human marker genes in zebrafish. Human and zebrafish HSCs show conservation of transcriptional profiles, and we uncover collectin subfamily member 11 (colec11) as a novel, conserved marker for zebrafish HSCs. To demonstrate the power of scRNA‐seq to study liver fibrosis using zebrafish, we performed scRNA‐seq on our zebrafish model of a pediatric liver disease with mutation in mannose phosphate isomerase (MPI) and characteristic early liver fibrosis. We found fibrosis signaling pathways and upstream regulators conserved across MPI‐depleted zebrafish and human HSCs. CellPhoneDB analysis of zebrafish transcriptome identified neuropilin 1 as a potential driver of liver fibrosis. Conclusion: This study establishes the first scRNA‐seq atlas of the adult zebrafish liver, highlights the high degree of similarity to human liver, and strengthens its value as a model to study liver fibrosis.
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