ArticleToxicology2017
Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells.
Article in Toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 52 citations in OpenAlex.
- Dihydroorotate dehydrogenase (DHODH) regulates trophoblast syncytialization through organelle stress-induced cellular senescence.FEBS open bio · 2026Article
- NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.Journal of experimental & clinical cancer research : CR · 2025Article
- 7-Hydroxycannabidiol and 7-carboxycannabidiol induced cytotoxicity via apoptosis and endoplasmic reticulum stress in human hepatic cells.Archives of toxicology · 2025Article
- Leflunomide-Induced Weight Loss: Involvement of DAHPS Activity and Synthesis of Aromatic Amino Acids.Metabolites · 2024Article
- Article
- Anti-tumor effect and hepatotoxicity mechanisms of psoralen.Frontiers in pharmacology · 2024Review
- Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury.Molecules (Basel, Switzerland) · 2023Review
- Milk Exosomal miR-27b Worsen Endoplasmic Reticulum Stress Mediated Colorectal Cancer Cell Death.Nutrients · 2022Article
- Article
- Reestablish immune tolerance in rheumatoid arthritis.Frontiers in immunology · 2022Review
- Cellular Stress Pathways Are Linked to Acetamiprid-Induced Apoptosis in SH-SY5Y Neural Cells.Biology · 2021Article
- Cell Death and Transcriptional Responses Induced in Larvae of the NematodePharmaceuticals (Basel, Switzerland) · 2021Article
- Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review.International immunopharmacology · 2021Review
- A mechanism of perhexiline's cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway.Chemico-biological interactions · 2021Article
- Identification of Translational microRNA Biomarker Candidates for Ketoconazole-Induced Liver Injury Using Next-Generation Sequencing.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Research Progress of Pharmacogenomics in Drug-Induced Liver Injury.Frontiers in pharmacology · 2021Review
- CpG Oligodeoxynucleotides Attenuate OVA-Induced Allergic Airway Inflammation via Suppressing JNK-Mediated Endoplasmic Reticulum Stress.Journal of asthma and allergy · 2021Article
- Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity.Cellular oncology (Dordrecht, Netherlands) · 2020Article
- Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline.Toxicology in vitro : an international journal published in association with BIBRA · 2020Article
- Immunomodulatory action of excretory-secretory products of Angiostrongylus cantonensis in a mouse tumour model.Parasitology research · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Leflunomide, used for the treatment of rheumatoid arthritis, has been reported to cause severe liver problems and liver failure; however, the underlying mechanisms are not clear. In this study, we used multiple approaches including genomic analysis to investigate and characterize the possible molecular mechanisms of the cytotoxicity of leflunomide in hepatic cells. We found that leflunomide caused endoplasmic reticulum (ER) stress and activated an unfolded protein response, as evidenced by increased expression of related genes including CHOP and GADD34; and elevated protein levels of typical ER stress markers including CHOP, ATF-4, p-eIF2α, and spliced XBP1. The secretion of Gaussia luciferase was suppressed in cells treated with leflunomide in an ER stress reporter assay. Inhibition of ER stress with an ER stress inhibitor 4-phenylbutyrate, and knockdown of ATF-4 and CHOP genes partially protected cells upon leflunomide exposure. In addition, both genomic and biochemical analyses revealed that JNK and ERK1/2 of MAPK signaling pathways were activated, and both contributed to the leflunomide-induced cytotoxicity. Inhibiting JNK activation using a JNK inhibitor attenuated the ER stress and cytotoxicity of leflunomide, whereas inhibiting ERK1/2 using an ERK1/2 inhibitor or ERK1/2 siRNA increased the adverse effect caused by leflunomide, suggesting opposite roles for the two pathways. In summary, our data indicate that both ER stress and the activation of JNK and ERK1/2 contribute to leflunomide-induced cytotoxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.