自身免疫性肝炎 (AIH) 的特点是免疫驱动的肝脏破坏和细胞因子产生，是一种进行性炎症性肝脏疾病，可能发展为肝硬化或肿瘤。然而，其潜在机制尚不清楚，而且这种疾病的治疗选择也有限。培美曲塞 (PEM) 是一种临床用于治疗多种肿瘤的抗叶酸药物，被发现可抑制核因子 (NF)-κB 信号通路，而核因子 (NF)-κB 信号通路在 AIH 的发展中发挥重要作用。在这里，我们使用刀豆蛋白 A (Con A) 诱导的肝炎小鼠模型（一种成熟的 AIH 模型）研究了 PEM 对免疫介导的肝损伤的影响。小鼠以 12 小时的间隔接受 3 次腹腔 PEM 注射，两小时后，用 Con A 进行攻击。10 小时后收集肝脏样本和血清。结果表明，PEM 显着提高了小鼠的存活率并降低了血清转氨酶水平。此外，PEM 可有效缓解氧化应激，减少组织病理学肝损伤，并减轻肝细胞凋亡。值得注意的是，它减少了肝脏中 M1 型巨噬细胞的活化。促炎细胞因子和与 M1 巨噬细胞相关的基因，如肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL)-6、IL-12、IL-1β 和诱导型一氧化氮合酶 (iNOS) 的表达也减少了。最后，结果表明PEM通过调节NF-κB信号通路来调节M1巨噬细胞的活化。总体而言，这些结果表明，PEM 通过 NF-κB 信号通路抑制 M1 巨噬细胞活化，有效预防 Con A 诱导的免疫介导的肝损伤，并表明 PEM 作为临床环境中 AIH 的实用治疗选择的潜力。版权所有 © 2023 年。由 Elsevier B.V 出版。

Autoimmune hepatitis (AIH), characterized by immune-driven liver destruction and cytokine production, is a progressive inflammatory liver condition that may progress to hepatic cirrhosis or tumors. However, the underlying mechanism is not well understood, and the treatment options for this disease are limited. Pemetrexed (PEM), a clinically used anti-folate drug for treating various tumors, was found to inhibit the nuclear factor (NF)-κB signaling pathways that exert an important role in the development of AIH. Here, we investigated the impact of PEM on immune-mediated hepatic injuries using a murine model of Concanavalin A (Con A)-induced hepatitis, a well-established model for AIH. Mice received intraperitoneal PEM injections 3 times at 12-hour intervals, and two hours later, they were challenged with Con A. Liver samples and serum were collected after 10 h. The results indicate that PEM significantly improved mouse survival rates and lowered serum transaminase levels. Moreover, PEM effectively alleviated oxidative stress, reduced histopathological liver damage, and mitigated hepatocyte apoptosis. Notably, it reduced the activation of M1-type macrophages in the liver. The expression of proinflammatory cytokines and genes associated with M1 macrophages, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-12, IL-1β, and inducible nitric oxide synthase (iNOS), was also decreased. Finally, the results indicated that PEM regulates M1 macrophage activation by modulating the NF-κB signaling pathways. Overall, these results demonstrate that PEM effectively guards against immune-mediated hepatic injuries induced by Con A by inhibiting M1 macrophage activation through the NF-κB signaling pathways and indicate the potential of PEM as a practical treatment option for AIH in clinical settings.Copyright © 2023. Published by Elsevier B.V.