ArticleAutophagy2024
Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.
Article in Autophagy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Therapeutic gases and the Nrf2/Keap1 pathway: direct thiol modification vs . indirect modulation.Medical gas research · 2027Review
- Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.Translational lung cancer research · 2026Review
- AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.Journal of physiology and biochemistry · 2026Review
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Avian pathogenic Escherichia coli virulence protein Hcp2a induces incomplete autophagy in chicken HD11 cells.Poultry science · 2026Article
- The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.Toxicological research · 2026Review
- RAS signaling in lung adenocarcinoma is defined by lineage context and DUSP4 loss.JCI insight · 2026Article
- Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.PloS one · 2026Article
- Lysosomal checkpoints in renal autoimmunity: from antigen processing to metabolic-immune crosstalk.Frontiers in immunology · 2026Review
- Nrf2/Keap1 Signaling Axis in the Brain: Master Regulator of Oxidative Stress in Neurodegenerative and Psychiatric Disorders.Molecular neurobiology · 2025Review
- In Vivo and In Vitro Antioxidant Effects ofAntioxidants (Basel, Switzerland) · 2025Article
- STK11 Alleviates Pulmonary Inflammation During Acute Lung Injury by Phosphorylating AMPK to Activate Autophagy in A549 Cell Model.Journal of inflammation research · 2025Article
- A novel effect of bevacizumab in reducing characteristic pigmentation in Peutz-Jeghers syndrome: a case report and literature review.Frontiers in oncology · 2025Article
- New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis.Biomolecules & therapeutics · 2025Review
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- Unveiling ferroptosis: a new frontier in skin disease research.Frontiers in immunology · 2024Review
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca
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