Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

中文翻译：

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Interleukin-21 受体信号传导通过诱导免疫抑制 IgA+ B 细胞促进代谢功能障碍相关的脂肪性肝炎驱动的肝细胞癌

免疫监视失调与代谢功能障碍相关脂肪性肝炎 (MASH) 驱动的肝细胞癌 (HCC) 的发展密切相关；然而，其根本机制仍不清楚。在此，我们的目的是确定白细胞介素 21 受体 (IL-21R) 在 MASH 驱动的 HCC 中的作用。使用免疫组织化学染色评估人类 HCC 标本中 IL-21R 的临床意义。此外，在 STAM 模型中评估了小鼠中 IL-21R 的表达。此后，在IL-21R缺陷型小鼠和野生型对照小鼠之间应用两种不同的MASH驱动的HCC小鼠模型，以探索IL-21R在MASH驱动的HCC中的作用。为了进一步阐明 IL-21R 影响 MASH 驱动的 HCC 的潜在机制，进行了全转录组测序、流式细胞术和过继性淋巴细胞转移。最后通过流式细胞术、酶联免疫吸附试验、免疫荧光染色、染色质免疫沉淀试验和蛋白质印迹法探讨IL-21R诱导IgA+B细胞的机制。 IL-21R高表达的HCC患者表现出较差的无复发生存率、晚期TNM分期和严重的脂肪变性。此外，IL-21R 被证明在小鼠肝脏肿瘤中表达上调。特别是，IL-21R 的消除可阻止 MASH 驱动的肝癌发生，并显着减少脂质积累。此外，在没有 IL-21R 的情况下，由于免疫抑制性 IgA+ B 细胞的减少，细胞毒性 CD8+ T 淋巴细胞的活化增强。从机制上讲，IL-21R-STAT1-c-Jun/c-Fos 调节轴在 MASH 驱动的 HCC 中被激活，从而促进 Igha 的转录，从而诱导 IgA+ B 细胞。 IL-21R 通过在 MASH 驱动的肝癌发生中诱导 IgA+ B 细胞发挥促癌作用。靶向 IL-21R 信号传导代表了癌症治疗的潜在治疗策略。