ArticleArchives of toxicology2016
Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-κB activation and sensitizes toward TNFα-induced cytotoxicity.
Article in Archives of toxicology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 62 citations in OpenAlex.
- Systematic comparison of temporal hepatotoxicant-induced gene network responses across 3 liver test systems.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Systematic review on genetic polymorphisms associated with idiosyncratic drug-induced liver injury (iDILI): iDILInet as an interactive visualization tool.Acta pharmaceutica Sinica. B · 2026Article
- Hepato-renal Protective Effect of Glutamine in Oxidative Stress Rat Model by Elevating the Glutamine-Glutathione Axis.International journal of preventive medicine · 2026Article
- Nephroprotective Impacts ofFood science & nutrition · 2025Article
- The Regulation of the NF-κB p65 and Nrf2/HO-1 Signaling Pathways by Fucoxanthin in Human THP-1 Monocyte Macrophages Under a Lipopolysaccharide-Induced Inflammation Model.Foods (Basel, Switzerland) · 2025Article
- An Nrf2-NF-κB Crosstalk Controls Hepatocyte Proliferation in the Normal and Injured Liver.Cellular and molecular gastroenterology and hepatology · 2025Article
- Screening impacts of Tilmicosin-induced hepatic and renal toxicity in rats: protection by Rhodiola rosea extract through the involvement of oxidative stress, antioxidants, and inflammatory cytokines biomarkers.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- Boosting impacts ofToxicology research · 2024Article
- Hybrid non-animal modeling: A mechanistic approach to predict chemical hepatotoxicity.Journal of hazardous materials · 2024Article
- Protective impacts ofToxicology research · 2024Article
- A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories.Inflammopharmacology · 2023Article
- Ameliorative Impacts of Wheat Germ Oil against Ethanol-Induced Hepatic and Renal Dysfunction in Rats: Involvement of Anti-Inflammatory, Anti-Apoptotic, and Antioxidant Signaling Pathways.Life (Basel, Switzerland) · 2022Article
- Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure.Scientific reports · 2022Article
- Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis.Journal of medicinal chemistry · 2022Article
- Conjugation of Diclofenac with Novel Oleanolic Acid Derivatives Modulate Nrf2 and NF-κB Activity in Hepatic Cancer Cells and Normal Hepatocytes Leading to Enhancement of Its Therapeutic and Chemopreventive Potential.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity.Frontiers in cell and developmental biology · 2021Review
- Review
- Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies.Clinical and translational allergy · 2020Review
- Andrographolide sodium bisulfate attenuates UV‑induced photo‑damage by activating the keap1/Nrf2 pathway and downregulating the NF‑κB pathway in HaCaT keratinocytes.International journal of molecular medicine · 2020Article
- Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial DysfunctionFrontiers in pharmacology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-κB, respectively. Here, we systematically investigated Nrf2 and NF-κB signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-κB activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-κB, GFP-tagged p65, upon TNFR signaling induced by TNFα using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-κB nuclear translocation, yet reversely, activation of NF-κB by TNFα did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNFα-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNFα, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-κB signaling may be pivotal in the regulation of DILI. We propose that the NF-κB-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines.
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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.