Background and Aims: HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX₃CR1⁺ macrophages to protumorigenic properties in the peritumoral area. Approach and Results: In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism–related genes. Flow cytometry analysis showed significantly increased frequencies of CD14⁺CD11b⁺HLA-DR⁻ macrophages with CX₃CR1 in the HCC adjacent region where α-smooth muscle actin–expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX₃CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX₃CR1⁺Ly6C⁺ macrophages was mostly observed with decreased CD8⁺ T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX₃CR1⁺Ly6C⁺ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX₃CR1⁺Ly6C⁺ macrophages and human blood CD14⁺ cells, leading to the suppression of CD8⁺ T-cell proliferation. Moreover, genetic deficiency of CX₃CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. Conclusions: We showed that CX₃CR1⁺Ly6C⁺ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX₃CR1⁺Ly6C⁺ macrophages, subsequently depriving CD8⁺ T cells of arginine and promoting HCC.

Although tremendous research has reported the protective effects of natural compounds in nonalcoholic fatty liver disease (NAFLD), there is still no approved drug. This study aimed to examine the efficacy of Panax ginseng in NAFLD in preclinical studies. A total of 41 studies were identified by searching the PubMed, Web of Science, and Cochrane Library databases. The methodological quality was assessed by the risk of bias tool from the Systematic Review Center for Laboratory Animal Experimentation. The standardized mean difference (SMD) with a 95% confidence interval was calculated, and the random effects model was used to examine overall efficacy or heterogeneity. The publication bias was analyzed by Egger’s test. The results showed that Panax ginseng treatment significantly reduced the systemic levels of alanine aminotransferase (SMD: −2.15 IU/L; p < 0.0001), aspartate aminotransferase (SMD: −2.86 IU/L; p < 0.0001), triglyceride (SMD: −2.86 mg/dL; p < 0.0001), total cholesterol (SMD: −1.69 mg/dL; p < 0.0001), low-density lipoprotein (SMD: −1.46 mg/dL; p < 0.0001), and fasting glucose (SMD: −1.45 mg/dL; p < 0.0001) while increasing high-density lipoprotein (SMD: 1.22 mg/dL; p = 0.0002) in NAFLD regardless of animal models or species. These findings may suggest that Panax ginseng is a promising therapeutic agent for NAFLD treatment.