SIRT6/NRF2/GPX4 signaling pathway
The SIRT6/NRF2/GPX4 signaling pathway is a three-tier cascade coordinating antioxidant defense and suppression of ferroptosis.
The SIRT6/NRF2/GPX4 signaling pathway is a three-tier cascade coordinating antioxidant defense and suppression of ferroptosis. SIRT6 is an NAD⁺-dependent deacetylase acting on chromatin — principally at H3K9 and H3K56 — which makes its activity a function of cellular NAD⁺ and therefore of metabolic state; it acts upstream to promote activity of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Nrf2 is otherwise held down by kelch like ECH associated protein 1 (KEAP1), which targets it for continuous degradation; relieving that repression allows Nrf2 to accumulate in the nucleus and transcribe cytoprotective genes, among them GPX4 (glutathione peroxidase 4), the selenoenzyme that reduces lipid peroxides and is the principal brake on ferroptotic death.
The output is protection against lipid peroxidation and oxidative stress: raising Gpx4 reduces accumulation of lipid reactive oxygen species and the ferroptotic death that follows. It does not by itself lower Fe²⁺, which is set by separate iron-handling systems — ferritin storage, ferritinophagy and transporter-mediated import and export — so the axis limits the consequences of labile iron rather than the iron itself.
Its relevance is greatest where ferroptosis and oxidative stress drive pathology: type 2 diabetes-induced endothelial dysfunction, ischemic injury, heart failure and cancer therapy resistance. Interventions reported to engage it include folic acid, berberine, ergothioneine and selenium nanoparticles — the last acting on the limiting element of Gpx4 itself, since a selenoenzyme cannot be made without selenium. As with other Nrf2-centered axes, the therapeutic direction is context-dependent: reinforcement protects normal tissue under oxidative insult, while the same activity in a tumor sustains resistance to treatments intended to kill it.
Where the papers sit
11 papers from the last 6 months study SIRT6/NRF2/GPX4 signaling pathway directly · updated from PubMed 12 Oct 2026
Study type 0 clinical trials · 1 observational · 9 preclinical · 1 unclassified
Themes 3 themes
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Nrf2-Mediated Tissue Protection
Nrf2 activation is a convergent strategy for limiting oxidative injury in diabetes, stroke, wounds and radiation exposure. Small molecules such as isoorientin and ergothioneine are paired with pathway modulation, while berberine plus metformin shows interest in combination effects. Selenium nanoparticles and temperature-responsive patches extend the approach toward targeted or stimulus-responsive delivery. Neuroprotection, cognitive recovery and tissue regeneration remain the main endpoints.
5 papers · 45.5%
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Oxidative Stress and Ferroptosis
Redox control is being pursued across tissue injury and cancer therapy, linking ROS handling, ferroptosis and GPX4 regulation. Nrf2 activation and ROS-responsive or inhaled nanodelivery recur as ways to localize antioxidant effects. GPX4 promoter hypermethylation in heart failure adds an epigenetic disease marker to this framework. The disease contexts and interventions remain too diverse to identify one preferred treatment.
4 papers · 36.4%
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Ferroptosis in Lung Cancer
Ferroptosis is being explored as a therapeutic vulnerability in lung adenocarcinoma, particularly to improve cisplatin response. DLX6 inhibition sensitizes tumors through GPX4-dependent ferroptosis, placing antioxidant defense at the center of drug resistance. HNF4α is also identified as a target linked to cellular plasticity and treatment vulnerability. The evidence remains early, with the relationship between these transcriptional regulators and ferroptosis still open.
2 papers · 18.2%
Papers
The 11 papers from the last 6 months that study SIRT6/NRF2/GPX4 signaling pathway directly, newest first, by theme and by study type. Study types come from PubMed publication types and MeSH headings.
By theme
Nrf2-Mediated Tissue Protection (5)
- Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. Metabolic brain disease · 17 Jul 2026 PMID 42467274
- Supra-additive neuroprotective effects of berberine-metformin combination in diabetic encephalopathy: Chou-Talalay synergy quantification, AMPK-Nrf2 axis modulation, and pharmacokinetic verification. Metabolic brain disease · 2 Jul 2026 PMID 42390621
- Radio-Protective Effects of Selenium Nanoparticles Synthesized Using Aqueous Extract of Rhodiola on Mice Irradiated by 60Co γ-Rays. ACS biomaterials science & engineering · 23 Jun 2026 PMID 42335449
- Ergothioneine exerts neuroprotection in experimental ischemic stroke via activation of PI3K/Akt/Nrf2 pathway. Neuroreport · 29 May 2026 PMID 42214028
- Body temperature-responsive Janus patches accelerate diabetic wound regeneration via coupling mechanical transduction and biochemical pathways. Journal of controlled release : official journal of the Controlled Release Society · 11 May 2026 PMID 42114775
Oxidative Stress and Ferroptosis (4)
- Site-specific promoter hypermethylation of GPX4 in heart failure with reduced ejection fraction (HFrEF): nonlinear dose-response with hepatic and coagulation markers. Molecular biology reports · 10 Jul 2026 PMID 42430008
- Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy. ACS nano · 11 May 2026 PMID 42114042
- Research on Therapeutic Strategy of Inhalable Cell Membrane-Coated Nanodelivery Complexes Mediating Nrf2 Pathway for Ameliorating Pulmonary Fibrosis. ACS applied materials & interfaces · 17 Apr 2026 PMID 41992617
- ROS-Responsive Hydrogel Delivering Bio-Nanoselenium for Targeted Therapy of UVB-Induced Skin Photodamage. ACS applied materials & interfaces · 15 Apr 2026 PMID 41983715
Ferroptosis in Lung Cancer (2)
- Inhibition of DLX6 sensitizes lung adenocarcinoma to cisplatin via GPX4-dependent ferroptosis. Cellular oncology (Dordrecht, Netherlands) · 15 Jul 2026 PMID 42455236
- Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma. The Journal of clinical investigation · 1 Jul 2026 PMID 42383354
By study type
Observational studies and case reports (1)
- Site-specific promoter hypermethylation of GPX4 in heart failure with reduced ejection fraction (HFrEF): nonlinear dose-response with hepatic and coagulation markers. Molecular biology reports · 10 Jul 2026 PMID 42430008
Preclinical: animal, cell and lab studies (9)
- Isoorientin inhibits oxidative stress to ameliorate cognitive dysfunction in type 2 diabetes mice via GSK3β/Nrf2 axis. Metabolic brain disease · 17 Jul 2026 PMID 42467274
- Supra-additive neuroprotective effects of berberine-metformin combination in diabetic encephalopathy: Chou-Talalay synergy quantification, AMPK-Nrf2 axis modulation, and pharmacokinetic verification. Metabolic brain disease · 2 Jul 2026 PMID 42390621
- Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma. The Journal of clinical investigation · 1 Jul 2026 PMID 42383354
- Radio-Protective Effects of Selenium Nanoparticles Synthesized Using Aqueous Extract of Rhodiola on Mice Irradiated by 60Co γ-Rays. ACS biomaterials science & engineering · 23 Jun 2026 PMID 42335449
- Ergothioneine exerts neuroprotection in experimental ischemic stroke via activation of PI3K/Akt/Nrf2 pathway. Neuroreport · 29 May 2026 PMID 42214028
- Body temperature-responsive Janus patches accelerate diabetic wound regeneration via coupling mechanical transduction and biochemical pathways. Journal of controlled release : official journal of the Controlled Release Society · 11 May 2026 PMID 42114775
- Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy. ACS nano · 11 May 2026 PMID 42114042
- Research on Therapeutic Strategy of Inhalable Cell Membrane-Coated Nanodelivery Complexes Mediating Nrf2 Pathway for Ameliorating Pulmonary Fibrosis. ACS applied materials & interfaces · 17 Apr 2026 PMID 41992617
- ROS-Responsive Hydrogel Delivering Bio-Nanoselenium for Targeted Therapy of UVB-Induced Skin Photodamage. ACS applied materials & interfaces · 15 Apr 2026 PMID 41983715
Unclassified: not yet indexed with MeSH (1)
- Inhibition of DLX6 sensitizes lung adenocarcinoma to cisplatin via GPX4-dependent ferroptosis. Cellular oncology (Dordrecht, Netherlands) · 15 Jul 2026 PMID 42455236
Written from 11 PubMed abstracts, each one listed by PMID above. Published: 2026-06-15. Last written: 2026-08-26 by GPT. Corrections: 2026-08-08 by GPT. Drafted by language models from published abstracts; not medical advice.