非酒精性脂肪性肝炎（NASH）是肝硬化和肝细胞癌的主要原因，提出了重大且尚未解决的医学挑战。观察到 NASH 患者中程序性细胞死亡 4 (PDCD4) 表达下降，凸显了研究 NASH 潜在分子机制的必要性，这表明 PDCD4 可能在维持肝脏健康方面发挥保护作用。在这项研究中，我们确定 PDCD4 是小鼠 NASH 发展的天然抑制剂。 PDCD4 的缺失会导致 NASH 的自发进展。值得注意的是，由于 CIITA 激活，PDCD4 缺陷的肝细胞显示出主要组织相容性复合物 II 类 (MHCII) 表达升高，表明 PCCDC4 可以防止肝细胞异常转化为抗原呈递细胞 (APC)。细胞共培养实验表明，缺乏PDCD4的肝细胞类似于APC，可以通过呈递多种肽直接激活CD4 T细胞，导致炎症因子的释放。此外，细胞和动物研究表明 CIITA 会促进肝细胞中的脂质积累并加剧 NASH 进展。总之，我们的研究结果揭示了 PDCD4 在 NASH 发展过程中调节 CIITA 和 MHCII 表达的新作用，为 NASH 治疗提供了新的治疗方法。版权所有 © 2024。由 Elsevier Inc. 出版。

Nonalcoholic steatohepatitis (NASH) is a primary cause of liver cirrhosis and hepatocellular carcinoma, presenting a significant and unmet medical challenge. The necessity to investigate the molecular mechanisms underlying NASH is highlighted by the observed decrease in programmed cell death 4 (PDCD4) expression in NASH patients, suggesting that PDCD4 may play a protective role in maintaining liver health. In this study, we identify PDCD4 as a natural inhibitor of NASH development in mice. The absence of PDCD4 leads to the spontaneous progression of NASH. Notably, PDCD4-deficient hepatocytes display elevated major histocompatibility complex class II (MHCII) expression due to CIITA activation, indicating that PCDC4 prevents the abnormal transformation of hepatocytes into antigen-presenting cells (APCs). Cell co-culture experiments reveal that hepatocytes lacking PDCD4, which resemble APCs, can directly activate CD4+ T cells by presenting multiple peptides, resulting in the release of inflammatory factors. Additionally, both cellular and animal studies show that CIITA promotes lipid accumulation in hepatocytes and exacerbates NASH progression. In summary, our findings reveal a novel role of PDCD4 in regulating CIITA and MHCII expression during NASH development, offering new therapeutic approaches for NASH treatment.Copyright © 2024. Published by Elsevier Inc.