ArticleCell biology and toxicology2024
Triptolide induces hepatotoxicity by promoting ferroptosis through Nrf2 degradation.
Article in Cell biology and toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- A 'three-axis synergy' immunotherapeutic strategy for malignant bone tumors based on natural bioactives and bioactive materials.Bioactive materials · 2026Review
- Salvianolic acid B suppresses non-small cell lung cancer growth by promoting Nrf2 proteasomal degradation and triggering autophagy-dependent ferroptosis.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Liver-Directed Cyp2e1 RNA Interference Attenuates Hepatotoxicity Induced by Triptolide, a Bioactive Diterpenoid fromPharmaceuticals (Basel, Switzerland) · 2026Article
- Curcumin Protects Mouse Spermatogonia from Triptolide-Induced Injury Through Modulation of Ferroptosis-Related Pathways.Biology · 2026Article
- Reprogramming of the mToxics · 2026Article
- Triptolide: A Narrative Review of Its Traditional Use, Derivatives, Pharmacology, Antitumor Effect, and Clinical Applications.Cancers · 2026Review
- Pleiotropic pharmacological activities and multiple-organ toxicities of triptolide: a programmed cell death perspective.Chinese medicine · 2026Review
- Targeting Galectin-1 with Triptolide Induces Ferroptosis in Oral Squamous Cell Carcinoma.Cancers · 2026Article
- Serum miR-381-3p: Diagnostic Role and Mechanisms in Liver Transplant Ischemia-reperfusion Injury.Journal of clinical and translational hepatology · 2026Article
- Anti-Cancer Research Progress of Triptolide: Mechanisms of Action, Structural Modifications, Nanodelivery Systems and Clinical Challenges.Drug design, development and therapy · 2026Review
- From immunosuppression to immune reprogramming: is triptolide a potential "immune reset" agent in autoimmune diseases?Immunologic research · 2025Review
- Article
- Association Between Iron Overload and the Risk of Ocular Hypertension, Primary Open-Angle Glaucoma, and Normal-Tension Glaucoma.Translational vision science & technology · 2025Article
- Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2 and Therapeutic Strategies.Cancers · 2025Review
- [Catalpol reduces liver toxicity of triptolide in mice by inhibiting hepatocyte ferroptosis through the SLC7A11/GPX4 pathway: testing theNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2025Article
- SIRT7-mediated NRF2 deacetylation promotes antioxidant response and protects against chemodrug-induced liver injury.Cell death & disease · 2025Article
- Article
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9 authors.
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Abstract
backgroundTriptolide (TP), a principal active substance from Tripterygium wilfordii, exhibits various pharmacological effects. However, its potential hepatotoxicity has always been a significant concern in clinical applications. PURPOSE: This research aimed to explore the involvement of ferroptosis in TP-mediated hepatic injury and the underlying mechanisms.
methodsIn this study, in vitro and in vivo experiments were involved. Hepatocyte damage caused by TP was evaluated using MTT assays, liver enzyme measurement and H&E staining technique. Ferroptosis was assessed by measuring iron level, lipid peroxide, glutathione (GSH), mitochondrial morphology and the key protein/mRNA expression implicated in ferroptosis. To verify the contribution of ferroptosis to TP-induced liver damage, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) and a plasmid for overexpressing glutathione peroxidase 4 (GPX4) were employed. Subsequently, nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice and Nrf2 overexpression plasmid were utilized to investigate the underlying mechanisms. Nontargeted lipidomics was used to analyze lipid metabolism in mouse liver. Moreover, the cellular thermal shift assay (CETSA), cycloheximide (CHX) and MG132 treatments, and immunoprecipitation (IP) assays were applied to validate the binding of TP to Nrf2 and their interactions.
resultsTP triggered ferroptosis in hepatocytes, as indicated by iron accumulation and lipid peroxidation. Ferroptosis was responsible for TP-induced hepatic injury. During the process of TP-induced liver damage, the Nrf2 signaling pathway was significantly suppressed. Notably, the deletion of Nrf2 in mice aggravated the extent of liver injury and ferroptosis associated with TP, whereas enhancing Nrf2 expression in cells significantly reduced TP-induced ferroptosis. Additionally, dysregulation of lipid metabolism was associated with TP-induced liver injury. TP may directly bind to Nrf2 and enhance its degradation through the ubiquitin-proteasome pathway, thereby inhibiting or reducing Nrf2 expression.
conclusionIn summary, the suppression of Nrf2 by TP facilitated the occurrence of ferroptosis, resulting in liver damage.
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