{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:37:21Z","timestamp":1790671041248,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174209"],"award-info":[{"award-number":["82174209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82174209"],"award-info":[{"award-number":["82174209"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Tripterygium glycoside tablets (TGT), a representative formulation derived from Tripterygium wilfordii Hook F, have limited clinical application due to adverse reproductive toxicity. In previous studies investigating the effects of TGT on chronic kidney disease (CKD), it was found that both TGT and its alkaloid-enriched fraction (AEF) induced testicular atrophy, suggesting that AEF may be the material basis for the reproductive toxicity of TGT. Therefore, the reproductive toxicity of AEF was investigated in depth. This study established a CKD rat model to investigate the toxic effects of TGT, AEF, and the non-alkaloid-enriched fraction (NAEF) on the reproductive system during CKD treatment. Network toxicology and metabolomics were combined to elucidate the underlying mechanisms of AEF-induced reproductive toxicity. The results showed that both TGT and AEF significantly reduced testicular index and sperm concentration, causing seminiferous tubule atrophy and disrupting the levels of testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Furthermore, TGT, AEF, and NAEF all significantly inhibited the proliferation of GC-1 cells. Network toxicology indicated that AEF modulates targets such as SRC, AKT, and HSP90AA1, thereby influencing pathways including the PI3K-AKT signaling pathway and pathways in cancer. Metabolomics obtained 89 differential metabolites of AEF, which were enriched in glycerophospholipid, linoleic acid, and arachidonic acid metabolism, a finding consistent with the constructed \u201cmetabolite\u2013enzyme\u2013reaction\u2013gene\u201d network. In summary, AEF exerts reproductive toxicity primarily by disrupting hypothalamic\u2013pituitary\u2013testicular axis homeostasis and perturbing glycerophospholipid, linoleic acid, and arachidonic acid metabolism.<\/jats:p>","DOI":"10.3390\/toxins18040175","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T01:12:33Z","timestamp":1775437953000},"page":"175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Network Toxicology and Metabolomics Reveal the Reproductive Toxicity Mechanisms of Alkaloid-Enriched Fractions in Tripterygium Glycosides Tablets"],"prefix":"10.3390","volume":"18","author":[{"given":"Caiyao","family":"Han","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3576-1760","authenticated-orcid":false,"given":"Zhuohua","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"He","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China"},{"name":"Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China"},{"name":"Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1002\/med.21762","article-title":"Tripterygium wilfordii: An inspiring resource for rheumatoid arthritis treatment","volume":"41","author":"Zhang","year":"2021","journal-title":"Med. 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