{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:10:00Z","timestamp":1788916200159,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Program for HUST Academic Frontier Youth Team","award":["2018QYTD12"],"award-info":[{"award-number":["2018QYTD12"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: 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. Methods: 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 (p &lt; 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. Results: 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. Conclusions: These effects may be related to the observed weight loss induced by leflunomide.<\/jats:p>","DOI":"10.3390\/metabo14110645","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T10:37:35Z","timestamp":1732099055000},"page":"645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiaoyu","family":"Guo","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0144-6676","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongli","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyun","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyun","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zejun","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"},{"name":"Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-4578","authenticated-orcid":false,"given":"Hongling","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Wuhan Polytechnic University, Wuhan 430023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1136\/ard-2022-222486","article-title":"Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: A prospective, multicentre, randomised trial and long-term follow-up","volume":"81","author":"Fu","year":"2022","journal-title":"Ann. 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