SIRT6/NRF2/GPX4 signaling pathway

Overview

The SIRT6/NRF2/GPX4 signaling pathway is a redox-regulatory axis implicated in cellular defense against oxidative stress and ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. In this pathway, SIRT6 is positioned upstream as a regulator of antioxidant and stress-response programs, NRF2 functions as a central transcriptional controller of cytoprotective genes, and GPX4 acts as a key effector enzyme that limits lipid peroxide accumulation. Together, these components help preserve membrane integrity and cellular viability under conditions of metabolic, inflammatory, or toxic stress.

Recent biomedical studies have linked this pathway to diseases characterized by oxidative injury and ferroptotic damage, including type 2 diabetes, diabetic nephropathy, endothelial dysfunction, renal injury, skin photodamage, and cancer therapy resistance. In these contexts, modulation of the SIRT6/Nrf2/GPx4 axis has been associated with changes in ferroptosis-related markers such as SLC7A11/XCT, ferritin heavy chain 1, transferrin receptor 1, glutathione balance, and lipid peroxidation products. The pathway is therefore being investigated both as a mechanistic node in disease biology and as a therapeutic target for antioxidant and anti-ferroptotic interventions.

Focus of Latest Publications

Recent publications have examined the SIRT6/NRF2/GPX4 signaling pathway primarily in the context of ferroptosis-related protection against diabetic vascular injury. In a study of type 2 diabetes-associated endothelial dysfunction, folic acid was tested in db/db or db/dm mice and in endothelial cells exposed to high-fat and high-glucose conditions. The authors reported that folic acid alleviated endothelial cell injury and ferroptosis, with effects linked to upregulation of the SIRT6/NRF2 pathway and attenuation of oxidative stress, Fe2+ accumulation, and lipid peroxidation. Importantly, inhibition of SIRT6 counteracted the protective effect of folic acid in vitro, supporting a functional role for this signaling axis in the observed endothelial protection.

Across the broader recent literature, GPX4 and NRF2 have continued to emerge as central nodes in redox and ferroptosis regulation, reinforcing the biological context in which the SIRT6/NRF2/GPX4 pathway is being studied. In UVB-induced skin photodamage, a ROS-responsive hydrogel delivering biogenic selenium nanoparticles was reported to confer therapeutic benefit by enhancing antioxidant defenses, inhibiting inflammation, and attenuating ferroptosis via GPX4/Nrf2 activation; genetic knockdown of GPX4 abolished the treatment effect. In pulmonary fibrosis, inhaled biomimetic nanoparticles carrying mulberrin and ADORA2B-targeted siRNA suppressed ROS production through Nrf2 pathway activation and reduced fibrotic injury. These studies do not directly assess SIRT6, but they underscore the recurring therapeutic relevance of NRF2- and GPX4-centered antioxidant signaling in oxidative stress-driven disease.

Additional publications have focused on GPX4 as a ferroptosis regulator in cancer and drug resistance. A bioorthogonal in situ PROTAC synthesis platform was designed to degrade GPX4 selectively in the tumor microenvironment, inducing ferroptosis and amplifying cuproptosis and photodynamic stress to promote immunogenic cell death. Separately, USP20 was identified as a resistance driver in tyrosine kinase inhibitor-treated cancers by deubiquitinating GPX4 and preventing its degradation, thereby sustaining antioxidant capacity and ferroptosis evasion. In a different ferroptosis-based strategy, metformin was combined with lactate oxidase to suppress SLC7A11-mediated glutathione synthesis and disable GPX4-mediated lipid peroxide detoxification, promoting tumor ferroptosis. Together, these studies place GPX4 at the center of multiple therapeutic approaches, while the folic acid study specifically links SIRT6/NRF2/GPX4 signaling to protection from diabetic endothelial ferroptosis.

Key Publications

NEWJul 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, 2026, PMID 42390621): "Berberine and metformin independently activate AMPK and may engage Nrf2-mediated antioxidant defenses, yet their combined neuroprotective interaction has not been formally quantified using validated synergy frameworks, nor has its pharmacokinetic basis been verified."
NEWJul Cellular plasticity as a therapeutic vulnerability: HNF4α is a key target in lung adenocarcinoma. (The Journal of clinical investigation, 2026, PMID 42383354): "HNF4α also promotes resistance to KRAS inhibition by increasing nuclear factor erythroid 2-related factor 2 (NRF2) activity."
May Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy. (ACS nano, 2026, PMID 42114042): "Targeting glutathione peroxidase 4 (GPX4) with traditional small-molecule inhibitors or conventional proteolysis-targeting chimeras (PROTACs) is limited by uncontrollable systemic toxicity."
Apr Research on Therapeutic Strategy of Inhalable Cell Membrane-Coated Nanodelivery Complexes Mediating Nrf2 Pathway for Ameliorating Pulmonary Fibrosis. (ACS applied materials & interfaces, 2026, PMID 41992617): "The nuclear factor erythroid 2-related factor 2 (Nrf2), a central regulator of antioxidant responses, represents a promising therapeutic target for IPF."
Apr ROS-Responsive Hydrogel Delivering Bio-Nanoselenium for Targeted Therapy of UVB-Induced Skin Photodamage. (ACS applied materials & interfaces, 2026, PMID 41983715): "Mechanistically, the hydrogel conferred therapeutic effects by enhancing antioxidant defenses, inhibiting inflammation and attenuating ferroptosis via GPx4/Nrf2 activation."
Apr Folic acid alleviates endothelial dysfunction caused by T2DM-induced ferroptosis by activating the SIRT6/NRF2/GPX4 signaling pathway. (Food & function, 2026, PMID 41906715): "The results indicated that folic acid alleviates endothelial cell injury and ferroptosis in T2DM by upregulating the SIRT6/NRF2 pathway and mitigating oxidative stress, Fe2+ accumulation and lipid peroxidation."
May USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers. (Redox biology, 2026, PMID 41844497): "We demonstrate TKI-resistant cells upregulate USP20, which binds and deubiquitinates the ferroptosis suppressor GPX4, preventing its proteasomal degradation."
May Combining lactate oxidase and metformin in cancer cell membrane-biomimetic liposomes for synergistic ferroptosis induction and hypoxia-alleviated cancer therapy. (Colloids and surfaces. B, Biointerfaces, 2026, PMID 41534499): "Concurrentl, MET suppresses SLC7A11-mediated GSH synthesis and disabling GPX4-mediated lipid peroxide detoxification."