ArticleMolecular pharmacology2012
Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity.
Article in Molecular pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 117 citations in OpenAlex.
- SRC-mediated phosphorylation of UBC9 regulates inflammatory and metabolic signaling in alcohol-associated liver disease.Science advances · 2026Article
- The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Mitochondrial P-JNK target, SAB (SH3BP5), in regulation of cell death.Frontiers in cell and developmental biology · 2024Review
- Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult.Molecular metabolism · 2023Article
- MLK3 localizes mainly to the cytoplasm and promotes oxidative stress injury via a positive feedback loop.Cell biochemistry and biophysics · 2023Article
- Downregulation of hepatic METTL3 contributes to APAP-induced liver injury in mice.JHEP reports : innovation in hepatology · 2023Article
- c-Antioxidants & redox signaling · 2023Article
- Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3β phosphorylation and mitochondrial translocation.Experimental & molecular medicine · 2023Article
- An update on animal models of liver fibrosis.Frontiers in medicine · 2023Review
- Platanosides, a Potential Botanical Drug Combination, Decrease Liver Injury Caused by Acetaminophen Overdose in Mice.Journal of natural products · 2022Review
- Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options.Journal of Zhejiang University. Science. B · 2022Review
- The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity.Life (Basel, Switzerland) · 2021Article
- A multiplier peroxiporin signal transduction pathway powers piscine spermatozoa.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mitochondrial protein adduct and superoxide generation are prerequisites for early activation of c-jun N-terminal kinase within the cytosol after an acetaminophen overdose in mice.Toxicology letters · 2021Article
- Cell Death in Liver Diseases: A Review.International journal of molecular sciences · 2020Review
- The development and hepatotoxicity of acetaminophen: reviewing over a century of progress.Drug metabolism reviews · 2020Review
- Pre-treatment twice with liposomal clodronate protects against acetaminophen hepatotoxicity through a pre-conditioning effect.Liver research (Beijing, China) · 2020Article
- Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients.Cancer chemotherapy and pharmacology · 2020Observational
- Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injury.The Journal of clinical investigation · 2019Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
c-Jun NH(2)-terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3β activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wild-type mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.
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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.