理由：Sma 母亲针对十肢麻痹同源物 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) 中发挥复杂且矛盾的作用。然而，Smad4在肝细胞中调节肝癌发生的具体作用仍不清楚。方法：在肝细胞特异性 Smad4 缺失（AlbSmad4-/-）小鼠中建立二乙基亚硝胺/四氯化碳诱导的 HCC 模型，并监测肝脏肿瘤的发生。通过免疫荧光和荧光激活细胞分选（FACS）检查免疫细胞浸润。分析细胞因子分泌、糖酵解、信号通路和单细胞RNA测序的机制。结果：AlbSmad4-/- 小鼠表现出明显更少且更小的肝脏肿瘤结节、更少的纤维化、减少的骨髓源性抑制细胞浸润和增加的 CD8 T 细胞浸润。肝细胞中的 Smad4 缺失增强了 C-X-C 基序配体 10 (CXCL10) 的分泌，促进 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点 (mTOR)/乳酸脱氢酶 A (LDHA) 通路，从而增加了 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。结论：我们的结果表明，肝细胞中的 Smad4 可促进肝癌发生，是预防和治疗 HCC 的潜在候选靶点。© 作者。

Rationale: 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. Methods: A diethylnitrosamine/carbon tetrachloride-induced HCC model was established in mice with hepatocyte-specific Smad4 deletion (AlbSmad4-/-) 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. Results: AlbSmad4-/- 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. Conclusion: Our results demonstrate that Smad4 in hepatocytes promotes hepatocarcinogenesis and is a potential and candidate target for the prevention and therapy of HCC.© The author(s).