This study investigates the role of oxytocin in alleviating liver fibrosis and identifies hepatic macrophages as the central hub in this process. Previous studies have shown that oxytocin can reverse liver fibrosis in mice, but the underlying mechanism was unclear due to the absence of oxytocin receptors in hepatic stellate cells, the primary effector cells in liver fibrosis. The current study used single-cell sequencing to generate a comprehensive map of cell populations in fibrotic livers and found that oxytocin promotes a phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. This switch is validated using myeloid-specific oxytocin receptor knockout mice and liver fibrosis animal models. The study further demonstrates that calcium influx induced by oxytocin receptor activation activates the orphan nuclear receptor NR4A1, which controls the macrophage phenotypic switch. Specifically, calcium ions activate CREB, a key regulator of NR4A1 expression. These findings establish hepatic macrophages as the central hub in the oxytocin-mediated alleviation of liver fibrosis and reveal a novel pathway by which oxytocin regulates macrophage phenotype. The potential clinical applications of oxytocin and its analogues in treating liver fibrosis are discussed.This study investigates the role of oxytocin in alleviating liver fibrosis and identifies hepatic macrophages as the central hub in this process. Previous studies have shown that oxytocin can reverse liver fibrosis in mice, but the underlying mechanism was unclear due to the absence of oxytocin receptors in hepatic stellate cells, the primary effector cells in liver fibrosis. The current study used single-cell sequencing to generate a comprehensive map of cell populations in fibrotic livers and found that oxytocin promotes a phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. This switch is validated using myeloid-specific oxytocin receptor knockout mice and liver fibrosis animal models. The study further demonstrates that calcium influx induced by oxytocin receptor activation activates the orphan nuclear receptor NR4A1, which controls the macrophage phenotypic switch. Specifically, calcium ions activate CREB, a key regulator of NR4A1 expression. These findings establish hepatic macrophages as the central hub in the oxytocin-mediated alleviation of liver fibrosis and reveal a novel pathway by which oxytocin regulates macrophage phenotype. The potential clinical applications of oxytocin and its analogues in treating liver fibrosis are discussed.