肝细胞癌（HCC）是癌症死亡的主要原因，与病毒性肝炎，非酒精性脂肪性肝炎（NASH）和酒精性脂肪性肝炎（ASH）有关，这些都会触发内质网应激，肝细胞死亡，炎症和代偿性增殖。利用内质网应激易感MUP-uPA小鼠，我们建立了内质网应激和高营养物共同引起NASH和HCC的模型，但是单个应激因子（例如ATF4）对HCC的贡献及其作用机制仍未知。将ATF4在肝细胞中缺失的MUP-uPA小鼠（MUP-uPA/Atf4Δhep）和对照MUP-uPA / Atf4F/F小鼠饲喂高脂饮食（HFD）诱导NASH诱导HCC，并注射二乙基亚硝胺（DEN）模拟致癌物诱导HCC。进行组织学，生化和RNA测序分析以确定和定义ATF4诱导的SLC7A11表达在肝癌发生中的作用。通过在ATF4缺失的原代肝细胞和小鼠肝脏中重组SLC7A11来研究其对铁死亡和HCC发展的影响。肝细胞ATF4消融抑制了脂肪肝的发生，但增加了铁死亡的易感性，导致HCC发展加速。尽管ATF4激活了许多基因，但仅仅通过表达ATF4靶标之一SLC7A11即可逆转铁死亡易感性并促进HCC发展，SLC7A11编码半胱氨酸 - 谷氨酸抗体xCT的亚单位，需要谷胱甘肽（GSH）合成。铁死亡抑制剂也减轻了肝损伤和炎症。ATF4与SLC7A11的数量在人HCC和NASH患者的肝脏中呈正相关。尽管ATF4在HCC中上调表达，但它在正常肝细胞中具有重要的保护功能。通过维持谷胱甘肽的产生，ATF4抑制了铁死亡依赖的炎症性细胞死亡，这已知会促进代偿性增殖和肝癌发生。铁死亡抑制剂或ATF4活化剂也可以减轻HCC的发生。

Hepatocellular carcinoma (HCC), a leading cause of cancer death, is associated with viral hepatitis, non-alcoholic and alcoholic steatohepatitis (NASH, ASH), all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as ATF4, to HCC and their underlying mechanisms of action remained unknown.Hepatocyte-specific ATF4 deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) and control MUP-uPA/Atf4F/F mice were fed high fat diet (HFD) to induce NASH-induced HCC, and Atf4F/F and Atf4Δhep mice were injected with diethylnitrosamine (DEN) to model carcinogen-induced HCC. Histological, biochemical, and RNA sequencing analyses were performed to identify and define the role of ATF4-induced SLC7A11 expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development.Hepatocyte ATF4 ablation inhibited hepatosteatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine-glutamate antiporter xCT, which is needed for glutathione (GSH) synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of NASH patients.Despite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset.Published by Elsevier B.V.