肝细胞癌（HCC）发病率迅速上升，主要是由于增加的肥胖导致非酒精性脂肪性肝炎（NASH），已知是HCC的危险因素。目前没有批准用于治疗NASH的方法。在这里，我们首次使用单细胞RNA测序对模拟人类NASH驱动的HCC的鼠模型进行表征，该模型为喂养高脂饮食的MUP-uPA小鼠。我们观察到一部分肝细胞中存在内质网（ER）应激和炎症激活，而这些肝细胞在进展为HCC的小鼠中富集。接下来，我们使用ER应激抑制剂BGP-15和可溶性gp130Fc对MUP-uPA小鼠进行治疗，后者是通过阻断白细胞介素-6转信号来抑制炎症的药物。这两种药物目前已进入2/3期人类临床试验，用于其他适应症。我们的研究结果显示，这种联合治疗逆转了NASH并减少了NASH驱动的HCC。我们的数据表明，这些药物可能成为NASH进展为HCC的潜在治疗方法。

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.