Targeting Ferroptosis, Pyroptosis, and NRF2 Signaling with Dietary Polyphenols in Diabetic Microvascular...

Diabetic retinopathy, diabetic kidney disease, and diabetic peripheral neuropathy remain major causes of visual loss, kidney failure, pain, disability, and reduced quality of life despite improvements in glycemic and cardiovascular risk management. Oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, lipid peroxidation, and sterile inflammation are shared features of these complications and converge on regulated cell-death programs. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 and complementary antioxidant systems are insufficient, whereas pyroptosis is an inflammatory lytic process executed by gasdermins after activation of inflammasome-associated or other inflammatory caspases. Nuclear factor erythroid 2-related factor 2 (NRF2) connects these pathways by regulating glutathione synthesis, lipid peroxide detoxification, iron handling, mitochondrial homeostasis, and redox-sensitive inflammatory signaling. Dietary polyphenols may influence this network through electrophilic or kinase-dependent NRF2 activation, preservation of the SLC7A11-glutathione-GPX4 axis, modulation of iron and lipid metabolism, and inhibition of NF-kappaB, TXNIP, NLRP3, caspase-1, and gasdermin signaling. This integrative review critically examines mechanistic, preclinical, and human evidence for these effects in the diabetic retina, kidney, and peripheral nerve. The strongest direct preclinical evidence currently concerns corilagin, resveratrol, isoquercetin, quercetin, epigallocatechin gallate, punicalagin, and selected anthocyanin-rich or phenolic extracts. Human studies suggest possible benefits for albuminuria, retinal edema, endothelial function, and neuropathic outcomes, but they rarely measure ferroptosis- or pyroptosis-specific biomarkers and their results are heterogeneous. The proposed ferroptosis-pyroptosis-NRF2 network should therefore be viewed as a biologically plausible integrative framework rather than a clinically validated linear pathway. Future trials require chemically characterized interventions, exposure biomarkers, tissue-relevant pharmacokinetics, prespecified regulated-cell-death panels, and clinically meaningful microvascular endpoints.