ArticleGenes & development2014
Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis.
Article in Genes & development, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 222 papers, 1 of them a synthesis that pooled it.
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Who cites it
222 citing papers in PubMed, 1 synthesis or guideline pooled it, 343 citations in OpenAlex.
- Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review.Cell communication and signaling : CCS · 2019Pooled it
- Research progress on the protective effect and oxidative stress mechanism of rutin against liver injury (Review).Molecular medicine reports · 2026Review
- Guaianolide dimer KGA-1002 targets GRP94 and triggers unfolded protein response-associated degradation of SKP2/AKT axis as a novel antihepatoma agent.Journal of advanced research · 2026Article
- Review
- Nrf2 as a therapeutic target of ginseng: A comprehensive review from preclinical evidence to clinical applications.Journal of ginseng research · 2026Review
- Nrf2 signaling pathway and its molecular regulatory mechanism.Journal of Zhejiang University. Science. B · 2026Review
- Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy.Antioxidants (Basel, Switzerland) · 2026Review
- SMURF2 attenuates NRF2-driven tumor progression by acting as a nuclear brake on NRF2 during cellular stress.Redox biology · 2026Article
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.Nature communications · 2025Article
- Bacteroides uniformis-generated hexadecanedioic acid ameliorates metabolic-associated fatty liver disease.Gut microbes · 2025Article
- Modulation of Nrf2 and Mitochondrial Function: Pharmacological Implications.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Tirzepatide protects the heart from doxorubicin-induced cardiotoxicity by modulating endoplasmic reticulum (ER) stress and HMGCoA reductase 1 expression.Cardiovascular research · 2025Article
- Delivery strategies to improve the pharmacological efficacy of NRF2 modulators: a review.RSC medicinal chemistry · 2025Review
- Diosmetin ameliorates inflammation and apoptosis in the pathomechanism of PCOS through the NRF2/AKT/PPARγ signalling pathway.Journal of ovarian research · 2025Article
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- Involvement of NRF2 and AMPK signaling in aging and progeria: a digest.Redox biology · 2025Review
- A fluorescence lifetime-based FLIM-timer for measuring the protein turnover of transcription factor Nrf2 in live cells.Scientific reports · 2025Article
- Targeting the Keap1/Nrf2 axis in cancer: molecular mechanisms and pharmacological interventions.Investigational new drugs · 2025Review
- SEL1L regulates ER homeostasis in Sertoli cells but is dispensable for their function.Molecular biology of the cell · 2025Article
162 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Down-regulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.
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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.