Peptide Redox Networks in Human Cells

Abstract

Cellular redox regulation is increasingly recognised as a spatially organised network in which oxidant production, thiol buffering, and selective signalling operate within compartment-specific microdomains rather than as uniform cellular processes. However, peptide-mediated mechanisms that actively define these local redox environments have not previously been integrated into a unified conceptual framework. This review introduces the concept of peptide redox networks, defined as peptide or protein systems whose local abundance, oxidation state, or proteolytic processing directly determines the amplitude, spatial confinement, or propagation of redox signalling within specific cellular microdomains. We evaluate the evidence supporting this framework and discuss its implications for mechanistic research and clinical translation. We synthesise current knowledge on glutathione, histidine-containing dipeptides, mitochondria-targeted peptides, and mitochondrial-derived peptides as complementary regulators of cellular redox homeostasis. Particular emphasis is placed on compartment-specific redox set points, NADPH-dependent buffering, ferroptosis vulnerability, mitochondrial quality control, and regulated thiol signalling. We further examine recent advances in redox proteomics, isotope tracing, and proteoform-aware analytical strategies, highlighting methodological challenges that influence data interpretation. Based on these considerations, we propose operational criteria for defining peptide redox network components, establish minimum reporting recommendations to improve reproducibility, and identify experimental approaches capable of distinguishing adaptive redox regulation from irreversible oxidative dysfunction. Peptide redox networks provide an integrative framework that links compartmental redox biology with peptide-mediated regulation across multiple physiological and pathological contexts. Adoption of standardised analytical approaches together with mechanistically defined network criteria should improve reproducibility, facilitate biomarker development, and accelerate the translation of peptide-based redox interventions into precision medicine.