甲氨蝶呤（MTX）引起的肝毒性是一种严重的不良反应，可能会限制其使用。因此，需要寻找适用于改善MTX引起的肝毒性的药物。左旋肉碱（LC）是一种具有有益代谢作用的天然分子，英夫利昔单抗（INF）是一种针对肿瘤坏死因子-α（TNF-α）的抗炎单克隆抗体。最近，发现Notch1/Hes-1信号通路在肝损伤的发病机制中起着关键作用。然而，其在MTX引起的肝毒性中的作用尚不清楚。本研究旨在评估LC或INF对MTX引起的肝毒性的调节作用，并重点探讨Notch1/Hes-1信号通路的潜在机制。将60只大鼠随机分为六组（n = 10）：（1）对照组（生理盐水）；（2）MTX组（20mg/kg MTX，腹腔注射[ip]，一次）；（3）LC组（500mg/kg ip，连续5天）；（4）INF组（7mg/kg INF ip，一次）；（5）MTX+LC组（20mg/kg ip，一次；500mg/kg ip，连续5天）；（6）MTX+INF组（20mg/kg ip，一次；7mg/kg INF ip，一次）。研究了氧化应激、炎症标志物和Notch1/Hes-1的指标。MTX导致Notch1和Hes-1蛋白的表达增加，并增加了肝脏中TNF-α、白细胞介素（IL）-6和IL-1β的水平。与LC或INF联合治疗显示出明显的抗氧化和抗炎作用。有趣的是，在LC联合治疗中，Notch1和Hes-1表达的下调更为显著，与INF相比。总之，LC或INF通过调节Notch1/Hes-1信号通路来减轻MTX引起的肝毒性。LC对MTX引起的肝毒性的改善效果明显优于INF。因此，LC联合治疗可能是一种安全和有效的治疗方法，可缓解MTX引起的肝毒性。©2023 Deutsche Pharmazeutische Gesellschaft.

Methotrexate (MTX)-induced hepatotoxicity is a serious adverse effect that may limit its use. Therefore, eligible drugs to ameliorate MTX-induced hepatotoxicity are required. l-Carnitine (LC) is a natural molecule with beneficial metabolic effects and infliximab (INF) is an anti-inflammatory monoclonal antibody against tumor necrosis factor-alpha (TNF-α). Recently, Notch1/Hes-1 signaling was found to play a key role in the pathogenesis of liver injury. However, its role in MTX-induced hepatotoxicity is unclear. This study aimed to evaluate the modulatory effects of LC or INF on MTX-induced hepatotoxicity and to explore the underlying mechanism with emphasis on the Notch1/Hes-1 signaling pathway. Sixty rats were randomized into six groups (n = 10): (1) control (saline); (2) MTX (20 mg/kg MTX, intraperitoneal [ip], once); (3) LC group (500 mg/kg ip, 5 days); (4) INF (7 mg/kg INF ip, once); (5) MTX+LC (20 mg/kg ip, once, 500 mg/kg ip, 5 days, respectively); (6) MTX+INF (20 mg/kg ip, once, 7 mg/kg INF ip, once, respectively). Oxidative stress, inflammatory markers, and Notch1/Hes-1 were investigated. MTX induced the expression of Notch1 and Hes-1 proteins and increased the levels of TNF-α, interleukin (IL)-6, and IL-1β in the liver. Cotreatment with LC or INF showed apparent antioxidant and anti-inflammatory effects. Interestingly, the downregulation of Notch1 and Hes-1 expression was more prominent in LC cotreatment as compared with INF. In conclusion, LC or INF attenuates MTX-induced hepatotoxicity through modulation of Notch1/Hes-1 signaling. The LC ameliorative effect against MTX-induced hepatotoxicity is significantly better than that of INF. Therefore, LC cotreatment may present a safe and therapeutically effective therapy in alleviating MTX-induced hepatotoxicity.© 2023 Deutsche Pharmazeutische Gesellschaft.