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BACKGROUND & AIMS: The liver is a vital organ composed of parenchymal, non-parenchymal, and immune cell populations. Single-cell sequencing approaches now provide the opportunity to understand how sex and age influence gene expression and cellular function across cell types within the liver.METHODS: We analyzed the cellular composition and intercellular interactions of the human liver through single-nucleus RNA sequencing, incorporating insights from 37 healthy liver samples. The dataset contains cells from female and male donors spanning more than seven decades of life, and analysis was performed to evaluate the impact of sex and age on differential gene expression, pathway enrichment, and predicted ligand-receptor and protein-protein interactions.RESULTS: Excluding the X and Y chromosomes, we identified 374 genes uniquely enriched in cells of the female liver and 520 genes enriched in cells of the male liver. Differential expression analysis defined unique circuitries enriched within each cell type between females and males and their impact on cell-cell communication and response to external signals, including enrichment of cholesterol metabolism (p <1.64 x 10), TGF-β receptor signaling (p <5.69 x 10), and fibronectin production (p <1.04 x 10) in female cells and bone morphogenic protein signaling (p <7.62 × 10) in male cells. With increasing age, we observe a greater diversity in gene expression, including enrichment of genes that regulate neuregulin signaling (p <7.81 × 10) at older ages, while genes regulating insulin growth factor signaling (p <2.44 × 10) are enriched at younger ages. Senescence signatures were also identified for each cell type within the liver.CONCLUSIONS: These results define the activities of healthy cell types within the liver across sex and age, providing a foundation for studies to examine how ancestry, geography, and disease states influence liver function within these contexts.IMPACT AND IMPLICATIONS: Our study provides a comprehensive single-cell analysis of 37 healthy human liver samples, revealing how sex and age influence gene expression profiles, cellular interactions, and signaling responses across liver cell types and subtypes. These insights are of particular significance for researchers investigating the influence of sex and age on cellular responses to injury and treatment of injury. Furthermore, this dataset serves as a healthy reference, enabling future studies to understand how ancestry, geography, and disease states shape liver biology in the context of age and sex.