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Sma mothers against decapentaplegic homologue 4 (Smad4) is a key mediator of the transforming growth factor β (TGF-β) pathway and plays complex and contradictory roles in hepatocellular carcinoma (HCC). However, the specific role of Smad4 in hepatocytes in regulating hepatocarcinogenesis remains poorly elucidated. A diethylnitrosamine/carbon tetrachloride-induced HCC model was established in mice with hepatocyte-specific Smad4 deletion (Alb) and liver tumorigenesis was monitored. Immune cell infiltration was examined by immunofluorescence and fluorescence activated cell sorting (FACS). Cytokine secretion, glycolysis, signal pathway, and single-cell RNA sequencing were analysed for mechanism. Alb mice exhibited significantly fewer and smaller liver tumor nodules, less fibrosis, reduced myeloid-derived suppressor cell infiltration and increased CD8 T cell infiltration. Smad4 deletion in hepatocytes enhanced C-X-C motif ligand 10 (CXCL10) secretion, promoting tumor necrosis factor-α (TNF-α) production in CD8 T cells. The loss of Smad4 activated the CXCL10/mammalian target of rapamycin (mTOR)/lactate dehydrogenase A (LDHA) pathway, which increased glycolytic activity in CD8 T cells. HCC patients with high Smad4 expression exhibited decreased CD8 T cell infiltration and altered glycolysis. Our results demonstrate that Smad4 in hepatocytes promotes hepatocarcinogenesis and is a potential and candidate target for the prevention and therapy of HCC.

Sma 母亲对抗 decapentaplegic 同源物 4（Smad4）是转化生长因子 β（TGF-β）途径的关键介质，在肝细胞癌（HCC）中发挥复杂而矛盾的作用。然而，Smad4 在肝细胞中调节肝癌发生的具体作用仍不清楚。

我们在具有肝细胞特异性 Smad4 缺失（Alb）的小鼠中建立了二乙基亚硝胺/四氯化碳诱导的 HCC 模型，并监测了肝肿瘤发生情况。通过免疫荧光和荧光激活细胞分选（FACS）检查免疫细胞浸润情况。分析了细胞因子分泌、糖酵解、信号通路和单细胞 RNA 测序，以探讨其机制。

Alb 小鼠的肝肿瘤结节数量明显减少且体积较小，纤维化程度降低，髓系来源抑制细胞浸润减少，CD8 T 细胞浸润增加。肝细胞中 Smad4 的缺失增强了 C-X-C 基序配体 10（CXCL10）的分泌，促进了 CD8 T 细胞中肿瘤坏死因子-α（TNF-α）的产生。Smad4 的缺失激活了 CXCL10/哺乳动物雷帕霉素靶蛋白（mTOR）/乳酸脱氢酶 A（LDHA）通路，增加了 CD8 T 细胞的糖酵解活性。Smad4 高表达的 HCC 患者表现出 CD8 T 细胞浸润减少和糖酵解改变。

我们的研究结果表明，肝细胞中的 Smad4 促进了肝癌的发生，是预防和治疗 HCC 的潜在候选靶点。