SIRT6/NRF2/GPX4 signaling pathway
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting SIRT6/NRF2/GPX4 signaling pathway (sorted by publication date).
Recent studies have highlighted the SIRT6/Nrf2/GPx4 axis as a protective pathway in ferroptosis-related vascular injury and oxidative stress-associated disease. In a study of type 2 diabetes mellitus–related endothelial dysfunction, folic acid was shown to alleviate endothelial cell injury and ferroptosis 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 upregulated the SIRT6/NRF2 pathway, reduced oxidative stress, Fe2+ accumulation, and lipid peroxidation, and that inhibition of SIRT6 counteracted the protective effect in vitro. This work supports a role for SIRT6-linked antioxidant signaling in limiting diabetes-associated endothelial damage.
Other recent publications have focused on GPX4-centered ferroptosis control in cancer and tissue injury. In a cancer therapy study, a logic-gated bioorthogonal nanosystem was designed to generate a GPX4-degrading PROTAC in situ within the tumor microenvironment, where concurrent cathepsin B activity and elevated glutathione enabled precise GPX4 targeting. This induced ferroptosis and was further amplified by copper-driven cuproptosis and chlorin e6-mediated photodynamic therapy, producing strong reactive oxygen species bursts and immunogenic cell death. In a separate cancer resistance study, USP20 was identified as a driver of tyrosine kinase inhibitor resistance by deubiquitinating GPX4 and preventing its degradation, thereby helping tumor cells evade ferroptosis; USP20 inhibition resensitized resistant tumors to sorafenib in vivo. In skin photodamage, a ROS-responsive hydrogel delivering bio-nanoselenium improved UVB-injured skin by enhancing antioxidant defenses and attenuating ferroptosis through GPX4/Nrf2 activation, with GPX4 knockdown abolishing the therapeutic effect.
Several studies also linked NRF2-centered antioxidant signaling to neuroprotection and fibrotic disease. Ergothioneine protected against experimental ischemic stroke by activating the PI3K/Akt/Nrf2 pathway, reducing infarct volume, improving cerebral perfusion, and attenuating glial activation; these effects were abolished by PI3K inhibition. In pulmonary fibrosis, inhaled biomimetic nanoparticles co-delivering mulberrin and ADORA2B-targeted siRNA suppressed reactive oxygen species production via Nrf2 activation, reduced M2 macrophage infiltration and profibrotic cytokine release, and ameliorated bleomycin-induced lung injury and fibrosis. Although not directly centered on SIRT6, these studies reinforce the broader relevance of NRF2-linked antioxidant defenses in limiting oxidative stress and tissue injury.
A related publication in diabetic encephalopathy examined berberine-metformin combination therapy and found supra-additive improvement in recognition memory, with neuroinflammatory suppression as the most robust mechanistic correlate. The authors noted that both agents may engage AMPK and Nrf2-mediated antioxidant defenses, but direct causal validation of the AMPK-Nrf2 axis was not performed. Together, these reports place SIRT6/NRF2/GPX4 signaling within a broader landscape of ferroptosis regulation, oxidative stress control, and disease-modifying strategies in diabetes, vascular injury, cancer, neurodegeneration, and fibrosis.
Result PMIDs
- [PMID 41780848]
- [PMID 41887114]
- [PMID 42002091]
- [PMID 42041149]
- [PMID 42099241]
- [PMID 42400944]
Target PMIDs
- [PMID 41534499]
- [PMID 41844497]
- [PMID 41906715]
- [PMID 41983715]
- [PMID 41992617]
- [PMID 42114042]
- [PMID 42214028]
- [PMID 42383354]
- [PMID 42390621]