Guo Xiaoyu, Wang Kai, Chen Hongli, Wang Na, Qiu Dongmei, Huang Haiyun, Luo Jiyu, Xu Ao, Xu Lingyun, Yu Zejun, Li Yuanyuan, Zhang Hongling
School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China.
School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China.
Metabolites. 2024 Nov 20;14(11):645. doi: 10.3390/metabo14110645.
Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced ( < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. These effects may be related to the observed weight loss induced by leflunomide.
来氟米特是一种异恶唑类免疫抑制剂，广泛用于治疗类风湿关节炎（RA）、银屑病关节炎（PsA）以及狼疮性肾炎（LN）等疾病。近年来，临床数据表明，部分患者服用来氟米特后出现明显体重减轻、肝损伤等严重不良反应。然而，来氟米特导致体重减轻的原因及机制尚不清楚。因此，我们使用小鼠动物模型给予来氟米特，观察到来氟米特实验组小鼠体重显著降低（<0.01）。在该动物实验中，采用代谢组学方法分析实验组小鼠肝脏，发现代谢途径的主要差异在于芳香族氨基酸代谢，证实来氟米特可抑制苯丙氨酸、酪氨酸和色氨酸生物合成的限速步骤。我们的研究表明，来氟米特抑制肠道微生物群中DAHPS的活性，扰乱苯丙氨酸、酪氨酸和色氨酸代谢以及碳水化合物和脂质代谢。来氟米特还通过激活PERK途径增加内质网应激，从而促进CHOP表达并增加凋亡诱导的肝损伤。这些作用可能与观察到来氟米特引起的体重减轻有关。
