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Updated: Sep 21, 2025
Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation
Vangelis Kondylis1,2,3,4, Farina Schneider2,3,4, Fabian Schorn2
1Institute for Genetics, University of Cologne, D-50674 Cologne, Germany.
Abstract:
SQSTM1/p62 is a multitasking protein that functions as an autophagy receptor, but also as a signaling hub regulating diverse cellular pathways. p62 accumulation in mice with autophagy-deficient hepatocytes mediates liver damage and hepatocarcinogenesis through Nrf2 overactivation, yet the role of the p62-Keap1-Nrf2 axis in cell death and hepatocarcinogenesis in the absence of underlying autophagy defects is less clear. Here, we addressed the role of p62 and Nrf2 activation in a chronic liver disease model, namely mice with liver parenchymal cell-specific knockout of NEMO (NEMOLPC-KO), in which we demonstrate that they show no inherent autophagy impairment. Unexpectedly, systemic p62 ablation aggravated the phenotype and caused early postnatal lethality in NEMOLPC-KO mice. Expression of a p62 mutant (p62ΔEx2-5), which retains the ability to form aggregates and activate Nrf2 signaling, did not cause early lethality, but exacerbated hepatocarcinogenesis in these mice. Our immunohistological and molecular analyses showed that the increased tumor burden was only consistent with increased expression/stability of p62ΔEx2-5 driving Nrf2 hyperactivation, but not with other protumorigenic functions of p62, such as mTOR activation, cMYC upregulation or increased fibrosis. Surprisingly, forced activation of Nrf2 per se did not increase liver injury or tumor burden in NEMOLPC-KO mice, suggesting that autophagy impairment is a necessary prerequisite to unleash the Nrf2 oncogenic potential in mice with autophagy-competent hepatocytes.
Insights
Systemic p62 ablation worsened liver disease in mice lacking NEMO, while a p62 mutant exacerbated cancer. Nrf2 activation alone did not increase liver injury, suggesting autophagy defects are needed for Nrf2
Area of Science:
- Cellular Biology
- Hepatology
- Oncology
Background:
- SQSTM1/p62 is a protein involved in autophagy and cellular signaling.
- p62 accumulation can cause liver damage and cancer via Nrf2 activation, but its role without autophagy defects is unclear.
- The p62-Keap1-Nrf2 axis is crucial in cellular pathways.
Purpose of the Study:
- To investigate the role of p62 and Nrf2 in chronic liver disease models lacking autophagy defects.
- To analyze the impact of p62 ablation and specific p62 mutants on liver injury and hepatocarcinogenesis.
- To determine the necessity of autophagy impairment for Nrf2's oncogenic potential in hepatocytes.
Main Methods:
- Utilized mice with liver parenchymal cell-specific knockout of NEMO (NEMOLPC-KO), which exhibit normal autophagy.
- Employed systemic p62 ablation and expression of a p62 mutant (p62ΔEx2-5) in NEMOLPC-KO mice.
- Conducted immunohistological and molecular analyses to assess liver damage, tumor burden, and signaling pathways (Nrf2, mTOR, cMYC).
Main Results:
- Systemic p62 ablation aggravated liver disease and caused early lethality in NEMOLPC-KO mice.
- A p62 mutant (p62ΔEx2-5) exacerbated hepatocarcinogenesis, linked to Nrf2 hyperactivation, but not other p62 functions.
- Forced Nrf2 activation alone did not increase liver injury or tumor burden in these autophagy-competent mice.
Conclusions:
- Autophagy competence in hepatocytes prevents Nrf2 from driving liver injury and cancer.
- Nrf2's oncogenic potential in the liver requires underlying autophagy impairment.
- The p62-Nrf2 axis plays a complex role in liver disease progression, dependent on autophagic status.
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