α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the SERPINA1 gene encoding AAT and the common mutant Z allele of SERPINA1 encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR‐34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser⁵⁷⁴. Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.

α1-抗胰蛋白酶（AAT）缺乏症是一种常见的遗传性疾病，表现为肺病和肝病。AAT 缺陷是由编码 AAT的SERPINA1基因和SERPINA1的常见突变 Z 等位基因的致病变异引起的编码 Z α1-抗胰蛋白酶 (ATZ)，这是一种形成肝毒性聚合物的蛋白质，保留在肝细胞的内质网中。PiZ 小鼠表达人类 ATZ，是研究 AAT 缺乏症人类肝脏疾病的宝贵模型。在这项研究中，我们调查了 PiZ 和对照小鼠之间 microRNA (miRNA) 的差异表达，发现 miR-34b/c 上调，其水平与肝内 ATZ 相关。此外，在 PiZ 小鼠肝脏中，我们发现驱动 microRNA-34b/c (miR-34b/c) 表达的 Forkhead Box O3 (FOXO3) 被激活，并且 miR-34b/c 表达依赖于 c-Jun N-末端激酶。 JNK) Ser ^{574 上的}磷酸化. PiZ 小鼠中 miR-34b/c 的缺失导致肝纤维化的早期发展和血小板衍生生长因子 (PDGF)（miR-34b/c 的靶标）的信号传导增加。FOXO3 的激活和 miR-34c 的增加在 AAT 缺乏的人的肝脏中得到证实。此外，在几种肝纤维化小鼠模型中检测到 JNK 激活的 FOXO3 和 miR-34b/c 上调。这项研究揭示了一条参与肝纤维化的途径，并可能与肝纤维化的遗传和获得性原因有关。