ArticleEMBO reports2025
KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.
Article in EMBO reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Autophagy in MASLD: A Metabolic and Precision Medicine Perspective.Liver international : official journal of the International Association for the Study of the Liver · 2026Review
- Regulation and roles of mammalian mitophagy.Nature reviews. Molecular cell biology · 2026Review
- Ro5-4864, a ligand of the mitochondrial translocator protein, protects against heart failure in mice via regulation of the p62-Keap1-Nrf2 axis.The Journal of physiology · 2026Article
- Phosphorylation tunes p62 condensates to drive autophagic degradation of ubiquitinated proteins.The EMBO journal · 2026Article
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Autophagy in the liver.Autophagy reports · 2026Review
- TRPA1 activation prompts lysosome-mediated Nrf2 degradation enhancing the killing of colorectal cancer cells.Redox biology · 2025Article
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Authors and funding
14 authors.
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Abstract
Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses reveal that p62 mutants unable to bind KEAP1 normalize the expression of NRF2 targets induced by defective autophagy. Autophagy deficiency causes organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly resulting from autophagy suppression markedly improved in mice carrying p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.
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