ArticleJournal of hepatology2020
NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly.
Article in Journal of hepatology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
72 citing papers in PubMed, 105 citations in OpenAlex.
- Unravelling the Therapeutic Potential of Cysteine for Cardiovascular Health.International journal of molecular sciences · 2026Review
- UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.Nature metabolism · 2026Article
- Adaptive oncogenesis of β-catenin emerges from declining liver tissue integrity.Nature communications · 2026Article
- Phosphorylation of YBX1 in the Kidneys is Altered in Legumain Knockout-Mice.Journal of proteome research · 2026Article
- Targeted activation of Nrf2 via sulforaphane-loaded exosomes attenuated azoospermic condition in the rat model.Scientific reports · 2026Article
- The PI3K pathway is a downstream effector of NRF2 activation in the esophagus.Translational oncology · 2026Article
- Unfolded protein response in bronchopulmonary dysplasia: mechanisms, pathways, and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Trigonelline activates NRF2 and awakens dormant ovarian follicles to promote pregnancy in aging mice.iScience · 2025Article
- Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.Pharmacological reviews · 2025Review
- Sex-specific metabolic responses to high-fat diet in mice with NOX4 deficiency.Redox biology · 2025Article
- ECM1 expression in chronic liver disease: Regulation by EGF/STAT1 and IFNγ/NRF2 signalling.JHEP reports : innovation in hepatology · 2025Article
- Loss of NUMB promotes hepatomegaly and hepatocellular carcinoma through the AKT/glycogen/hippo signaling.Oncogene · 2025Article
- Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.Nature cancer · 2025Article
- Single-cell and bulk transcriptome analysis unveils a ligand-receptor-based signature for prognostication and reveals that TREM1 controls the malignant behaviors of hepatocellular carcinoma.Acta biochimica et biophysica Sinica · 2025Article
- Article
- Identification of CD84 as a potent survival factor in acute myeloid leukemia.The Journal of clinical investigation · 2025Article
- Overview of Nrf2 as a target in ovary and ovarian dysfunctions focusing on its antioxidant properties.Journal of ovarian research · 2025Review
- Article
- Autophagy related 14 protects against liver injury by inhibiting multiple cell death pathways.eGastroenterology · 2025Article
- Kelch-like ECH-associated Protein 1/Nuclear Factor Erythroid 2-related Factor 2 Pathway and Its Interplay with Oncogenes in Lung Tumorigenesis.Journal of cancer prevention · 2024Review
12 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
14 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsHepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
methodsSince many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2
resultsHepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.
conclusionsNRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY: Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
Indexed as
Identifiers
What OpenQuestion holds
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.